N-naphthoylglycine derivatives

ABSTRACT

Herein disclosed are N-naphthoylglycine derivatives having aldose reductase inhibiting activity. The derivatives are useful for treating, diabetic complications.

This is a continuation of copending application Ser. No. 017,943, filedFeb. 24, 1987, now abandoned, which in turn is a division of copendingapplication Ser. No. 845,230, filed Mar. 28, 1986, now U.S. Pat. No.4,705,882, which in turn is a divisional of copending Ser. No. 756,139,filed Jul. 17, 1985, and issued as U.S. Pat. No. 4,600,724 on Aug. 5,1986, which in turn is a division of copending application Ser. No.530,457, filed Sept. 9, 1983, and issued as U.S. Pat. No. 4,568,693 onFeb. 4, 1986, which in turn is a division of copending application Ser.No. 321,306, filed Nov. 13, 1981, and issued as U.S. Pat. No. 4,439,617on Mar. 27, 1984.

Related Applications: Related hereto are U.S. patent application Ser.No. 321,304, now U.S. Pat. No. 4,391,816, U.S. patent application Ser.No. 321,303, now U.S. Pat. No. 4,447,452 and U.S. patent applicationSer. No. 321,300, now U.S. Pat. No. 4,391,825, all filed on the samedate as this application.

This application relates to N-naphthoylglycine derivatives,therapeutically acceptable salts thereof, a process for theirpreparation, and to methods of use and to pharmaceutical compositionsthereof. The derivatives have pharmacologic properties which render thembeneficial for the treatment of diabetes mellitus and associatedconditions.

For many years diabetes mellitus has been treated with two establishedtypes of drugs, namely insulin and oral hypoglycemic agents. These drugshave benefited hundreds of thousands of diabetics by improving theirwell-being and prolonging their lives. However, the resulting longevityof diabetic patients has led to complications such as neuropathy,nephropathy, retinopathy, cataracts and atherosclerosis. Thesecomplications have been linked to the undesirable accumulation ofsorbitol in diabetic tissue, which in turn result from the high levelsof glucose characteristic of the diabetic patient.

In mammals, including humans, the key enzyme involved in the conversionof hexoses to polyols (the sorbitol pathway) is aldose reductase. J. H.Kinoshita and collaborators, see J. H. Kinoshita et al., Biochem.Biophys. Acta. 158, 472 (1968) and references cited therein, havedemonstrated that aldose reductase plays a central role in the etiologyof galactosemic cataracts by effecting the conversion of galactose todulcitol (galactitol) and that an agent capable of inhibiting aldosereductase can prevent the detrimental accumulation of dulcitol in thelens. Furthermore, a relationship between elevated levels of glucose andan undesirable accumulation of sorbitol has been demonstrated in thelens, peripheral nervous cord and kidney of diabetic animals, see A.Pirie and R. van Heyningen, Exp. Eye Res., 3, 124 (1964); L. T. Chylackand J. H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward andR. W. R. Baker, Diabetol., 6, 531 (1970).

1,3-Dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid has been reported tobe an effective inhibitor of aldose reductase, see D. Dvornik et al.,Science, 182, 1146 (1973), and to be useful for the treatment ofdiabetic complications such as diabetic cataracts, neuropathy,nephropathy and retinopathy, see K. Sestanj, N. Simard-Duquesne and D.M. Dvornik, U.S. Pat. No. 3,821,383, Jun. 28, 1974. Other compoundshaving a similar utility are thethioxo-1H-benz[de]-isoquinoline-2(3H)-acetic acid derivatives of K.Sestanj, U.S. application Ser. No. 92,397, filed Nov. 8, 1979 and1H-benz[de]isoquinoline-2(3H)-acetic acid derivatives of K. Sestanj,U.S. application Ser. No. 92,604, filed Nov. 8, 1979.(S)-6-Fluoro-2,3-dihydrospiro(4H-1-benzopyran-4,4'-imidazolidine)-2',5'-dione(sorbinil) is still another compound that has received attention becauseof its aldose reductase inhibiting properties (see M. J. Peterson etal., Metabolism, 28 (Suppl. 1), 456 (1979). Accordingly, these compoundsrepresent an important new approach for the treatment of diabetesmellitus.

The present application discloses novel N-naphthoylglycine derivatives,represented below by formula I, which are effective inhibitors of aldosereductase. These new derivatives are structurally quite different fromthe above noted aldose reductase inhibitors. Close prior art compounds,on a structural basis, appear to be a group of thioacylaminoacids, e.g.N-phenylthioxomethyl-N-methylglycine, prepared by A. Lawson and C. E.Searle, J. Chem. Soc., 1556 (1957) as part of a chemical investigationof the chemical properties of such compounds. These last mentionedcompounds were prepared by thiobenzoylation of various amino acids with(thiobenzoylthio)acetic acid. An important structural difference betweenthese compounds and the present derivatives is the different type ofaromatic group substituted on the thione portion of the thioamide.Thioacylamides also have been reported [see Chem. Abstr., 86, 189582f(1977) for V. I. Cohen et al., Eur. J. Med. Chem., 5, 480 (1976) andChem. Abstr., 70, 11306a (1969) for von J. Voss and W. Walter, JustusLeibigs Ann. Chem., 716, 209 (1968)]. The structures of thethioacylamides of Cohen et al and Voss et al differ from the structureof the present derivatives by having at least a different type ofN-substitution. Another close prior art compound, on a structural basis,is N-[(1-naphthalenyl)carbonyl]glycine, [see Chem. Abstr., 61, 4333f(1964) for E. Cioranescu et al., Rev. Chim. Acad. Rep. PopulaireRoumaine, 7 (2), 755 (1962)]. The compound, which has been used as achemical intermediate, is distinguished from the compounds of thepresent invention by being an amide and not a thioamide.

SUMMARY OF THE INVENTION

The N-naphthoylglycine derivatives of this invention are represented byformula I ##STR1## wherein R¹ is hydrogen, lower alkyl, lower alkenyl orphenylmethyl; R² is hydrogen or lower alkyl; R³ is hydrogen, a loweralkoxy at position 6 of the naphthalene ring, or a substituent atposition 4, 5 or 8 of the naphthalene ring, the substituent beingselected from the group consisting of lower alkyl, lower alkoxy, halo,cyano, nitro and trihalomethyl, and R⁴ and R⁵ each is hydrogen; or R³and R⁴ each is a substituent at different positions selected frompositions 3 to 7 of the naphthalene ring, the substituents beingselected from the group consisting of lower alkyl, lower alkoxy, halo,trihalomethyl, (lower)alkoxy(lower)alkoxy, phenylmethoxy andphenylmethoxy substituted on the phenyl portion with a lower alkyl,lower alkoxy, halo or trihalomethyl, and R⁵ is hydrogen; or R³, R⁴ andR⁵ each is a substituent at different positions selected from positions4, 5 and 6 of the naphthalene ring, the substituent being selected fromthe group consisting of lower alkoxy, halo and trihalomethyl; or atherapeutically acceptable salt with an organic or inorganic base of thecompound of formula I wherein R² is hydrogen.

A group of preferred derivatives is represented by the compounds offormula I wherein R¹ is hydrogen, lower alkyl, 2-propenyl orphenylmethyl; R² is hydrogen or lower alkyl; R³ is hydrogen, a loweralkoxy at position 6 of the naphthalene ring, or a substituent atpositions 4, 5 or 8 of the naphthalene ring, the substituents beingselected from the group consisting of lower alkyl, lower alkoxy, halo,cyano, nitro and trifluoromethyl, and R⁴ and R⁵ each is hydrogen; or R³and R⁴ are a pair of substituents on the naphthalene ring, eachsubstituent being a different position of the ring, the pair ofsubstituents being selected from the group of pairs consisting of3-halo-4-lower alkoxy, 4,6-di(lower alkoxy), 5-halo-6-lower alkyl,5-halo-6-lower alkoxy, 5,7-dihalo, 5-(trifluoromethyl)-6-lower alkoxy,5-halo-6-(lower)alkoxy(lower)alkoxy,5-halo-6-[3-(trifluoromethyl)phenylmethoxy] and5-halo-6-(4-chlorophenylmethoxy), and R⁵ is hydrogen; or R³, R⁴ and R⁵each is a substituent on the naphthalene ring, each of the threesubstituents being at different positions on the ring, the threesubstituents being selected from the group of 4-loweralkoxy-5-halo-6-lower alkoxy and 4,6-di(loweralkoxy)-5-(trifluoromethyl); or a therapeutically acceptable salt withan organic or inorganic base of the compound of formula I wherein R² ishydrogen.

Another preferred group of the compounds is represented by the compoundsof formula I wherein R¹ is hydrogen, lower alkyl or phenylmethyl; R² ishydrogen or lower alkyl; R³ is 4-halo or 5-halo, and R⁴ and R⁵ each ishydrogen; or R³ and R⁴ are a pair of substituents on the naphthalenering selected from the group of pairs consisting of 3-halo-4-loweralkoxy, 4,6-di(lower alkoxy), 5-halo-6-lower alkyl, 5-halo-6-loweralkoxy, 5,7-dihalo and 5-(trifluoromethyl)-6-lower alkoxy, and R⁵ ishydrogen; or R³ is 4-lower alkoxy, R⁴ is 5-(trifluoromethyl) and R⁵ is6-lower alkoxy; or a therapeutically acceptable salt with an organic orinorganic base of the compound of formula I wherein R² is hydrogen.

A most preferred group of the compounds is represented by the compoundsof formula I wherein R¹ is lower alkyl; R² is hydrogen; R³ is 5-halo andR⁴ and R⁵ each is hydrogen; or R³ and R⁴ are a pair of substituents onthe naphthalene ring selected from the group of pairs consisting of3-halo-4-lower alkoxy, 5-halo-6-lower alkoxy and5-(trifluoromethyl)-6-lower alkoxy, and R⁵ is hydrogen; or R³ is 4-loweralkoxy, R⁴ is 5-(trifluoromethyl) and R⁵ is 6-lower alkoxy; or atherapeutically acceptable salt thereof with an organic or inorganicbase.

The compounds of formula I can be prepared by a process describedhereinafter.

A method is provided for preventing or relieving diabetes mellitusassociated complications in a diabetic mammal by administering to saidmammal a prophylactic or alleviating amount of the compound of formula Ior therapeutically acceptable salt thereof with an organic or inorganicbase.

The compound of formula I, or a therapeutically acceptable salt thereofwith an organic or inorganic base, when admixed with a pharmaceuticallyacceptable carrier, forms a pharmaceutical composition which can be usedaccording to the preceding method.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention, represented by formula I, can exist inrotameric forms. More explicitly, mesomerism imparts a partial doublebond character to the carbon-nitrogen bond of the thioamide group. Thispartial double bond character leads to restricted rotation about thecarbon nitrogen bond giving rise to cis and trans rotamers, therestricted rotation being augmented by the bulkiness of neighboringgroups. Interconversion of the rotamers is possible and is dependent onthe physical environment. As evidenced by its physical properties, thethermodynamically more stable rotamer exists exclusively in thecrystalline state of the compound and is the predominant isomer presentin equilabrated solutions. Furthermore, the more stable rotamer is themore pharmacologically active. The less stable rotamer can be separatedfrom the more stable rotamer by high performance liquid chromatographyor by thin layer chromatography. The rotameric forms are included withinthe scope of this invention. For brevity, the compounds of thisinvention, including their rotameric forms, are referred to herein ascompounds of formula I.

The term "lower alkyl" as used herein means a straight chain alkylradical containing from one to four carbon atoms or a branched chainalkyl radical containing three or four carbon atoms and includes methyl,ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl and1,1-dimethylethyl. Preferred lower alkyl radicals contain from one tothree carbon atoms.

The term "lower alkenyl" as used herein means a straight chain alkenylradical containing from two to six carbon atoms, or a branched chainalkenyl radical containing from four to six carbon atoms and includes,for example, ethenyl, 2-propenyl, 2-methyl-2-propenyl and2-ethyl-3-butenyl. Preferred lower alkenyl radicals contain two to threecarbon atoms.

The term "lower alkoxy" as used herein means a straight chain alkoxyradical containing from one to six carbon atoms, preferably one to threecarbon atoms, or a branched chain alkoxy radical containing three orfour carbon atoms, and includes methoxy, ethoxy, 1-methylethoxy, butoxyand hexanoxy.

The term "halo" as used herein means a halo radical and includes fluoro,chloro, bromo and iodo.

The term "ar" as used mean an aromatic radical containing at least onebenzene ring. The preferred aromatic radical is phenyl.

The compounds of formula I wherein R² is hydrogen form salts withsuitable therapeutically acceptable inorganic and organic bases. Thesederived salts possess the same activity as their parent acid and areincluded within the scope of this invention. The acid is transformed inexcellent yield into the corresponding therapeutically acceptable saltby neutralization of said acid with the appropriate inorganic or organicbase. The salts are administered usually in the same manner as theparent acid compounds. Suitable inorganic bases to form these saltsinclude, for example, the hydroxides, carbonates or bicarbonates of thetherapeutically acceptable alkali metals or alkaline earth metals, forexample, sodium, potassium, magnesium, calcium and the like. Suitableorganic bases include the following amines: benzylamine; lower mono-di-and trialkylamines, the alkyl radicals of which contain up to threecarbon atoms, such as methylamine, dimethylamine, trimethylamine,ethylamine, di- and triethylamine, methylethylamine, and the like;mono-, di- and trialkanolamines, the alkanol radicals of which containup to three carbon atoms, for example, mono-, di- and triethanolamine;alkylene-diamines which contain up to six carbon atoms, such ashexamethylenediamine; cyclic saturated or unsaturated bases containingup to six carbon atoms, such as pyrrolidine, piperidine, morpholine,piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such asN-methyl-morpholine and N-(2-hydroxyethyl)-piperidine, as well aspyridine. Furthermore, there may be mentioned the correspondingquaternary salts, such as the tetraalkyl (for example tetramethyl),alkyl-alkanol (for example methyltriethanol and trimethyl-monoethanol)and cyclic ammonium salts, for example the N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)-morpholinium N,N-di-methylmorpholinium,N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethylpiperidiniumsalts, which are characterized by having good water-solubility. Inprinciple, however, there can be used all the ammonium salts which arephysiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the acid of formula I in watercontaining at least one equivalent amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. Advantageously,the reaction is performed in a water-miscible, inert organic solvent,for example, methanol, ethanol, dioxane, and the like in the presence ofwater. For example, such use of sodium hydroxide, sodium carbonate orsodium bicarbonate gives a solution of the sodium salt. Evaporation ofthe solution or addition of a water-miscible solvent of a more moderatepolarity, for example, a lower alkanol, for instance, butanol, or alower alkanone, for instance, ethyl methyl ketone, gives the solidinorganic salt if that form is desired.

To produce an amine salt, the acidic compound of formula I is dissolvedin a suitable solvent of either moderate or low polarity, for example,ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least anequivalent amount of the amine corresponding to the desired cation isthen added to that solution. If the resulting salt does not precipitate,it can usually be obtained in solid form by addition of a misciblediluent of lower polarity, for example, benzene or petroleum ether, orby evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use substantiallyequivalent amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid of formula I with an equivalent amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

The compounds of this invention and their addition salts withpharmaceutically acceptable organic or inorganic bases may beadministered to mammals, for example, man, cattle or rabbits, eitheralone or in dosage forms, i.e., capsules or tablets, combined withpharmacologically acceptable excipients, see below. Advantageously thecompounds of this invention may be given orally. However, the method ofadministering the present active ingredients of this invention is not tobe construed as limited to a particular mode of administration. Forexample, the compounds may be administered topically directly to the eyein the form of drops of sterile, buffered ophthalmic solutions,preferably of pH 7.2-7.6. Also, they may be administered orally in solidform containing such excipients as starch, milk sugar, certain types ofclay and so forth. They may also be administered orally in the form ofsolutions or they may be injected parenterally. For parenteraladministration they may be used in the form of a sterile solution,preferably of pH 7.2-7.6, containing a pharmaceutically acceptablebuffer.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimal dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil efficacy is obtained. In general, the compounds of this inventionare most desirably administered at a concentration level that willgenerally afford effective results without causing any harmful ordeleterious side effects. For topical administration a 0.05-0.2%solution may be administered dropwise to the eye. The frequency ofinstillation varies with the subject under treatment from a drop everytwo or three days to once daily. For oral or parenteral administration apreferred level of dosage ranges from about 0.1 mg to about 200 mg perkilo of body weight per day, although aforementioned variations willoccur. However, a dosage level that is in the range of from about 0.5 mgto about 30 mg per kilo of body weight per day is most satisfactory.

Unit dosage forms such as capsules, tablets, pills and the like maycontain from about 5.0 mg to about 250 mg of the active ingredients ofthis invention, preferably with a significant quantity of apharmaceutical carrier. Thus, for oral administration, capsules cancontain from between about 5.0 mg to about 250 mg of the activeingredients of this invention with or without a pharmaceutical diluent.Tablets, either effervescent or noneffervescent, can contain betweenabout 5.0 to 250 mg of the active ingredients of this invention togetherwith conventional pharmaceutical carriers. Thus, tablets which may becoated and either effervescent or noneffervescent may be preparedaccording to the known art. Inert diluents or carriers, for example,magnesium carbonate or lactose, can be used together with conventionaldisintegrating agents for example, magnesium stearate.

Syrups or elixirs suitable for oral administration can be prepared fromwater soluble salts, for example, sodiumN-[[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycinate,and may advantageously contain glycerol and ethyl alcohol as solvents orpreservatives.

The compound of formula I, or a therapeutically acceptable salt thereof,also can be used in combination with insulin or oral hypoglycemic agentsto produce a beneficial effect in the treatment of diabetes mellitus. Inthis instance, commercially available insulin preparations or oralhypoglycemic agents, exemplified by acetohexamide, chlorpropamide,tolazamide, tolbutamide and phenformin, are suitable. The compound offormula I, or a therapeutically acceptable salt thereof, can beadministered sequentially or simultaneously with insulin or the oralhypoglycemic agent. Suitable methods of administration, compositions anddoses of the insulin preparation or oral hypoglycemic agent aredescribed in medical textbooks; for instance, "Physicians' DeskReference", 34 ed., Medical Economics Co., Oradell, N.J., U.S.A., 1980.When used in combination, the compound of formula I, or itstherapeutically acceptable salt, is administered as describedpreviously. The compound of formula I, or its therapeutically acceptablesalt, can be administered with the oral hypoglycemic agent in the formof a pharmaceutical composition comprising effective amounts of eachagent.

The aldose reductase inhibiting effects of the compounds of formula Iand their pharmaceutically acceptable salts with organic or inorganicbases can be demonstrated by employing an in vitro testing proceduresimilar to that described by S. Hayman and J. H. Kinoshita, J. Biol.Chem., 240,877 (1965). In the present case the procedure of Hayman andKinoshita is modified in that the final chromatography step is omittedin the preparation of the enzyme from bovine lens.

The following results were obtained when the foregoing listed compoundsof formula I were evaluated in the above in vitro test.

    __________________________________________________________________________                                          % Inhibition at                                                         Example                                                                             Different Molar                                                         In Which                                                                            Concentrations                          Compound of Formula I (R.sup.5 = H)                                                                           Compound                                                                            (in vitro)                              R.sup.1 R.sup.2                                                                          R.sup.3  R.sup.4     Is Prepared                                                                         10.sup.-5                                                                        10.sup.-6                                                                        10.sup.-7                         __________________________________________________________________________    CH.sub.3                                                                              CH.sub.3                                                                         5-Br     H            3     8                                      CH.sub.3                                                                              CH.sub.3                                                                         5-CF.sub.3                                                                             6-CH.sub.3 O                                                                              23     9                                      CH.sub.3                                                                              H  5-Br     H           32    93 87 47                                H       H  3-Cl     4-CH.sub.3 O                                                                              32    61 16                                   CH.sub.3                                                                              H  4-Br     H           33    91 77 32                                CH.sub.3                                                                              H  8-Br     H           34    88 75 24                                CH.sub.3                                                                              H  5-CH.sub.3 O                                                                           H           35    83 64 17                                CH.sub.3                                                                              H  5-CH.sub.3                                                                             H           36    89 74 26                                CH.sub.3                                                                              H  5-Br     6-CH.sub.3 (CH.sub.2).sub.4 O                                                             37    93 91 55                                CH.sub.3                                                                              H  5-CN     H           38    89 79 32                                CH.sub.3                                                                              H  5-NO.sub.2                                                                             H           39    91 83 43                                CH.sub.3                                                                              H  5-Cl     H           40    91 83 40                                CH.sub.3                                                                              H  5-Br     6-CH.sub.3 O                                                                              41    99 91 72                                CH.sub.3                                                                              H  5-Br     6-CH.sub.3  42    92 88 55                                CH.sub.3                                                                              H  H        H           43    85 51 13                                CH.sub.3                                                                              H  4-Cl     H           44    88 73 25                                CH.sub.3                                                                              H  3-Cl     4-CH.sub.3 O                                                                              45    85 78 33                                CH.sub.3                                                                              H  5-Cl     7-Cl        46    88 75 29                                CH.sub.3                                                                              H  5-I      6-CH.sub.3 O                                                                              47    98 95 72                                CH.sub.3                                                                              H  5-CN     6-CH.sub.3 O                                                                              48    98 93 74                                CH.sub.3                                                                              H  5-Br     6-CH.sub.3 O(CH.sub.2).sub.3 O                                                            49    92 87 38                                CH.sub.3                                                                              H  5-CH.sub.2 ═C(CH.sub.3)                                                            H           50    92 74 19                                CH.sub.3                                                                              H  5-(CH.sub.3).sub.2 CH                                                                  H           51    91 72 21                                CH.sub.3                                                                              H  5-CF.sub.3                                                                             6-CH.sub.3 O                                                                              52    98 94 65                                CH.sub.3                                                                              H  5-Br     6-[(3-CF.sub.3 --C.sub.6 H.sub.4)CH.sub.2 O]                                              53    86 37 11                                CH.sub.3                                                                              H  5-Br     6-[(4-Cl-C.sub.6 H.sub.4)CH.sub.2 O]                                                      53a   88 44  4                                CH.sub.3                                                                              H  5-CF.sub.3                                                                             H           53b   93 84 33                                H       H  5-Br     H           54    54 14                                   n-C.sub.3 H.sub.7                                                                     H  5-Br     H           55    91 70 19                                CH.sub.2 ═CH--CH.sub.2                                                            H  5-Br     H           56    92 77 27                                C.sub.2 H.sub.5                                                                       H  5-Br     H           57    85 72 24                                n-C.sub.4 H.sub.9                                                                     H  5-Br     H           58    86 65 19                                CH.sub.2 C.sub.6 H.sub.5                                                              H  5-Br     H           59    86 69 20                                __________________________________________________________________________

The aldose reductase inhibiting property of the compounds of thisinvention and the utilization of the compounds in preventing,diminishing and alleviating diabetic complications are demonstrable inexperiments using galactosemic rats, see Dvornik et al., cited above.Such experiments are exemplified hereinbelow after the listing of thefollowing general comments pertaining to these experiments:

(a) Four or more groups of six male rats, 50-70 g, Sprague-Dawleystrain, were used. The first group, the control group, was fed a mixtureof laboratory chow (rodent laboratory chow, Purina) and glucose at 20%(W/W %) concentration. The untreated galactosemic group was fed asimilar diet in which galactose is substituted for glucose. The thirdgroup was fed a diet prepared by mixing a given amount of the testcompound with the galactose containing diet. The concentration ofgalactose in the diet of the treated groups was the same as that for theuntreated galactosemic group.

(b) After four days, the animals were killed by decapitation. Theeyeballs were removed and punctured with a razor blade; the freed lenseswere rolled gently on filter paper and weighed. The sciatic nerves weredissected as completely as possible and weighed. Both tissues werefrozen and can be kept up to two weeks before being analyzed fordulcitol.

(c) The polyol determination was performed by a modification of theprocedure of M. Kraml and L. Cosyns, Clin. Biochem., 2,373 (1969). Onlytwo minor reagent changes were made: (a) The rinsing mixture was anaqueous 5% (w/v) trichloroacetic acid solution and (b) the stocksolution was prepared by dissolving 25 mg of dulcitol in 100 ml of anaqueous trichloroacetic acid solution. [N.B.: For each experiment theaverage value found in the tissue from rats fed the glucose diet wassubtracted from the individual values found in the corresponding rattissue to obtain the amount of polyol accumulated].

The following tabulated results show that the compounds of thisinvention diminish the accumulation of dulcitol in the lenses andsciatic nerves of rats fed galactose. The figures under L and Nrepresent the percentage decrease of dulcitol accumulation in thetissues of the lens and sciatic nerve, respectively, for treated rats ascompared to untreated rats.

    ______________________________________                                        Compound of Formula I  Dose                                                   R.sup.1                                                                            R.sup.2                                                                              R.sup.3  R.sup.4                                                                              R.sup.5                                                                              mg/kg/day                                                                             L   N                              ______________________________________                                        CH.sub.3                                                                           H      5-Br     H      H      189     24  79                                                                121     20  70                                                                62      14  53                             CH.sub.3                                                                           H      5-Cl     H      H      156     34  70                             CH.sub.3                                                                           H      5-Br     6-CH.sub.3 O                                                                         H      162     34  --                                                                58      --  78                                                                29      --  58                                                                15      --  32                             CH.sub.3                                                                           H      3-Cl     4-CH.sub.3 O                                                                         H      163     15  --                                                                25      --  27                             CH.sub.3                                                                           H      5-Cl     7-Cl   H      52      29  45                             CH.sub.3                                                                           H      5-CF.sub.3                                                                             6-CH.sub.3 O                                                                         H      26      15  94                             CH.sub.3                                                                           CH.sub.3                                                                             5-CF.sub.3                                                                             6-CH.sub.3 O                                                                         H      11      10  44                             CH.sub.3                                                                           H      5-CF.sub.3                                                                             H      H      11       2  36                             CH.sub.3                                                                           H      6-CH.sub.3 O                                                                           H      H      162     --  32                             CH.sub. 3                                                                          H      4-CH.sub.3 O                                                                           5-CF.sub.3                                                                           6-CH.sub.3 O                                                                         144     33  85                                                                25      --  48                             ______________________________________                                    

Process

The preparation of the compounds of formula I is illustrated by thefollowing scheme wherein R¹, R³, R⁴ and R⁵ are as defined hereinbeforeand COOR is an ester group which may be, for example, a lower alkyl oran ar(lower)-alkyl ester; i.e., R is lower alkyl or ar(lower)alkyl.##STR2##

More specifically, a process for preparing the compounds of formula Icomprises:

(a) reacting an amidoester of formula II wherein R¹, R³, R⁴ and R⁵ areas defined herein and R is lower alkyl or ar(lower)alkyl with phosphoruspentasulfide to give the corresponding thioxoester of formula IIIwherein R¹, R³, R⁴, R⁵ and R are as defined herein; or

(b) hydrolyzing the thioxoester of formula III wherein R¹, R³, R⁴, R⁵and R are as defined herein to obtain the corresponding compound offormula I wherein R¹, R³, R⁴ and R⁵ are as defined herein and R² ishydrogen; or

(c) hydrolyzing the amidoester of formula II wherein R¹, R³, R⁴, R⁵ andR are as defined herein to obtain the corresponding amidoacid of formulaIV wherein R¹, R³, R⁴ and R⁵ are as defined herein, and reacting thelast-named compound with phosphorus pentasulfide to obtain thecorresponding compound of formula I wherein R¹, R³, R⁴ and R⁵ are asdefined herein and R² is hydrogen.

Referring to the above section (a) of the last paragraph, thethioxoester of formula III includes those corresponding compounds offormula I wherein R² is lower alkyl, when R of the compound of formulaIII is lower alkyl. For clarity and convenience in the followingdiscussion of the process, these latter compounds of formula I areincluded in the discussion and preparation of the compounds of formulaIII.

Still more specifically, the starting material of formula II can beprepared by coupling a naphthalenecarboxylic acid of formula V whereinR³, R⁴ and R⁵ are as defined herein with an aminoacid ester of formulaVI wherein R¹ and R are as defined herein. ##STR3##

The compounds of formula V and VI are known or can be prepared by knownmethods. For example, see "Elsevier's Encyclopaedia of OrganicChemistry," F. Radt, Ed., Series III, Vol. 12B, Elsevier Publishing Co.,Amsterdam, 1953, pp 3965-4473. The preparation of a number of thenaphthalenecarboxylic acids is illustrated by examples 1 and 1a to 1jdescribed hereinafter. The coupling of the naphthalenecarboxylic acid Vand the amino acid ester VI is done preferably by the "carboxylactivation" coupling procedure. Descriptions of carboxyl-activatinggroups are found in general textbooks of peptide chemistry; for exampleK. D. Kopple, "Peptides and Amino Acids", W. A. Benjamin, Inc., NewYork, 1966, pp. 45-51, and E. Schroder and K. Luke, "The Peptides"; Vol.1, Academic Press, New York, 1965, pp. 77-128. Examples of the activatedform of the terminal carboxyl are the acid chloride, acid bromide,anhydride, azide, activated ester, or O-acyl urea obtained from adialkylcarbodiimide. Preferred activated forms of the carboxyl are theacid chloride or the 1-benzotriazolyl, 2,4,5-trichlorophenyl orsuccinimido activated esters.

Returning to the flow diagram again, the amidoester of formula II isreacted under anhydrous conditions with about two to five molarequivalents of phosphorus pentasulfide in an inert solvent, e.g. xyleneor toluene, to obtain the corresponding thioxoester of formula III. Thisreaction is performed conveniently at temperatures ranging from 80° toabout 150° C. and at times ranging from 20 minutes to four hours.Preferably, the reaction is performed in the presence of an organic basefor instance, N-ethyl morpholine, triethylamine or pyridine.

Thereafter, the thioxoester of formula III is hydrolyzed with ahydrolyzing agent to give the corresponding product of formula I inwhich R² is hydrogen. Generally speaking, this conversion is mostconveniently performed by employing a base as the hydrolyzing agent. Thehydrolysis is performed in the presence of sufficient water, followed byacidification of the reaction mixture, to yield the desired acid.However, it should be understood that the manner of hydrolysis for theprocess of this invention is not intended to be limited to basichydrolysis since hydrolysis under acidic conditions and othervariations, for example, treatment with lithium iodide in collidine (seeL. F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John Wileyand Sons, Inc., New York, 1969, pp. 615-617), also are applicable.Hydrolysis under acidic conditions is preferred when the ester is a tertbutyl ester.

For basic hydrolysis, a preferred embodiment involves subjecting theester to the action of a strong base, for example, sodium or potassiumhydroxide, in the presence of sufficient water to effect hydrolysis ofthe ester. The hydrolysis is performed using a suitable solvent, forexample, methanol, ethanol or 2-methoxyethanol. The reaction mixture ismaintained at a temperature of from about 25° to 100° C. or at thereflux temperature of the solvent employed until hydrolysis occurs.Usually from 10 minutes to 6 hours is sufficient for this hydrolysis.The reaction mixture is then rendered acidic with an acid, for example,acetic acid, hydrochloric acid or sulfuric acid to release the freeacid.

Alternatively, the amidoester of formula II can be hydrolyzed under thesame conditions as described hereinbefore to give the correspondingamidoacid of formula IV wherein R¹, R³, R⁴ and R⁵ are as defined herein.The latter compound, when reacted with phosphorus pentasulfide in themanner described hereinbefore, then gives the corresponding compound offormula I wherein R¹, R³, R⁴ and R⁵ are as defined herein and R² ishydrogen. Note that the standard first step of the work up of thepentasulfide reaction mixture requires that the reaction mixture bedecomposed in water. This action causes any corresponding thioacid,present in the reaction mixture as a result of the carboxy groupreacting with phosphorus pentasulfide, to be converted to the desiredcarboxylic acid.

The amidoacid of formula IV also can be prepared by a previouslyreported process involving the reaction of the appropriatenaphthalenecarboxylic acid chloride with the appropriate aminoacidcorresponding to the aminoacid ester of formula VI in the presence of abase (proton acceptor). This process has been used to prepareN-[(1-naphthalenyl)carbonyl]glycine, see Chem. Abstr., 61, 4333 f (1964)for E. Cioranescu, et al., Rev. Chim., Acad. Rep. Populaire Roumaine, 7(2), 755 (1962). However, this known process for preparingN-[(1-naphthalenyl)carbonyl]glycine is inferior, based on yields, to thepresent process.

An interesting aspect of this invention is that certain amidoesters offormula II and certain amidoacids of formula IV having the followingformula ##STR4## wherein R¹ is lower alkyl, lower alkenyl orphenylmethyl; R³ is a substituent at position 4, 5 or 8 of thenaphthalene ring, the substituent being selected from the groupconsisting of lower alkyl, lower alkoxy, halo, cyano, nitro andtrihalomethyl, and R⁴ and R⁵ each is hydrogen; or R³ and R⁴ each is asubstituent at different positions of the naphthalene ring, thepositions selected from positions 3 to 7 and the substituents beingselected from the group consisting of lower alkyl, lower alkoxy, halo,trihalomethyl, (lower)alkoxy(lower)alkoxy, phenylmethoxy andphenylmethoxy substituted on the phenyl portion with a lower alkyl,lower alkoxy, halo or trihalomethyl and R⁵ is hydrogen; or R³, R⁴ and R⁵each is a substituent at different positions selected from positions 4,5and 6 of the naphthalene ring, the substituent being selected from thegroup consisting of lower alkoxy, halo and trihalomethyl; and R ishydrogen or lower alkyl; or a therapeutically acceptable salt thereofwith an organic or inorganic base, also have aldose reductase inhibitingeffects. For example, in the above noted in vitro test, the followingresults were obtained for the amidoacids, described in example 60:

N-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine (10⁻⁵, 64%; 10⁻⁶,21%); and

N-[[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]carbonyl]-N-methylglycine(10⁻⁵, 94%; 10⁻⁶, 93%; 10⁻⁷, 60%). Accordingly, the latter amidoesters,amidoacids and the therapeutically acceptable salts with organic orinorganic bases, of the amidoacids are included within the scope of thisinvention.

The following examples illustrate further this invention.

EXAMPLE 1

5-(1-Methylethenyl)-1-naphthalenecarboxylic Acid (V, R³ =5-CH₂ =C(CH₃)and R⁴ and R⁵ =H)

In a nitrogen atmosphere, a solution of1-bromo-5-(1-methylethenyl)-naphthalene [14.21 g, described by W. F.Short and H. Wang, J. Chem. Soc., 991 (1950)] in diethyl ether (140 ml)was added dropwise to a mixture of ethyl magnesium bromide (preparedfrom 2.94 g of magnesium and 4.29 ml of ethyl bromide) in diethyl ether(30 ml) at 0° C. The mixture was stirred at 20° C. for 18 hr and thenheated at reflux for 1 hr. The cooled solution was poured onto an excessof solid carbon dioxide. The mixture was dissolved in diethyl ether. Theresulting solution was washed with a 2N aqueous solution of H₂ SO₄,brine and 10% aqueous NaHCO₃ (4x). The basic washes were combined andmade acidic (pH3) with 6N aqueous HCl. The resulting solid wascollected, washed with water and dried to give 9.7 g of the titlecompound; mp 138°-140° C.; NMR(CDCl₃) δ 2.15 (s, 3H), 5.0 and 5.38 (2s,2H), 8.0 (m, 6H), 10.75 (s, 1H).

EXAMPLE 1a

5-(1-Methylethyl)-1-naphthalenecarboxylic Acid (V, R³ =5-(CH₃)₂ CH andR⁴ and R⁵ =H)

5-(1-Methylethenyl)-1-naphthalenecarboxylic acid (4.36 g, described inExample 1), dissolved in ethanol (150 ml), was hydrogenated using 5%palladium on charcoal as catalyst at 20° C. Absorption of hydrogen wascomplete after 3 hr. The catalyst was removed by filtration. Thefiltrate was evaporated to give the title compound; mp 148°-150° C.;NMR(CDCl₃) δ 1.4 (d, J=7 Hz, 6H), 3.75 (septuplet, J=7 Hz, 1H), 8.0 (m,6H), 10.1 (s, 1H).

EXAMPLE 1b

5-Bromo-6-methoxy-1-naphthalenecarboxylic Acid (V, R³ =5-Br, R⁴ =6-CH₃ Oand R⁵ =H)

A solution of bromine (2.49 ml, 45 mmoles) in glacial acetic acid (50ml) was added dropwise to a stirred solution of6-methoxy-1-naphthalenecarboxylic acid [8.9 g, 44 mmoles, described byC. C. Price, et al., J. Am. Chem. Soc., 69, 2261 (1947)] in glacialacetic acid (300 ml), cooled in an ice bath. The resulting precipitatewas collected and washed with acetic acid and then water.Crystallization of collected precipitate from glacial acetic acid gavethe title compound; mp 262°-264° C.; NMR(DMSO-d₆) δ 3.96 (s, 3H),7.5-7.8 (m, 3H), 7.95 (d, 1H), 8.25 (d, 1H), 8.82 (d, 1H).

EXAMPLE 1c

5-Bromo-6-methyl-1-naphthalenecarboxylic Acid (V, R³ =5-Br, R⁴ =6-CH₃and R⁵ =H)

By following the procedure of Example 1b, but replacing6-methoxy-1-naphthalenecarboxylic acid with an equivalent amount of6-methyl-1-naphthalenecarboxylic acid, described by C. C. Price et al.,J. Am. Chem. Soc., 63, 1857 (1941), the title compound; mp 253°-255° C.[after crystallization from ethanolmethanol (3:1)], NMR (DMSO-d₆) δ 2.6(s, 3H), 8.0 (m, 5H), 10.5 (broad, 1H), was obtained.

EXAMPLE 1d

3-Chloro-4-methoxy-1-naphthalenecarboxylic Acid (V, R³ =3-Cl, R⁴ =4-CH₃O and R⁵ =H)

3-Chloro-4-methoxy-1-naphthalenecarboxaldehyde [15.5 g, 70.2 mmoles,described by A. J. Ablewhite and K. R. H. Wooldridge, J. Chem. Soc. (C),2488 (1967)] was added to a suspension of silver oxide in 10% sodiumhydroxide (16.9 g of sodium hydroxide in 170 ml of water) and dioxane(100 ml). The mixture was stirred and heated at 80° C. for 7 hr. Theprecipitate was removed by filtration through diatomaceous earth (soldunder the trademark Celite). The clear filtrate was evaporated todryness. The residue was dissolved in water. The solution was acidifiedand the resulting precipitate was separated by filtration. Theprecipitate was dissolved in ethyl acetate. The resulting solution wasextracted with saturated sodium bicarbonate solution. The combinedaqueous extracts were acidified. The resulting precipitate was separatedby filtration and recrystallized from ethanol-water to give the titlecompound; mp 187°-189° C.; NMR (DMSO-d₆) δ 4.0 (s, 3H), 8.15 (m, 5H),13.3 (broad 1H); IR (Nujol*) 2900, 1700, 1260, 1160 cm⁻¹ ; UVλmax (EtOH)303 (ε7,400), 231 (56,300); Anal. Calcd: C, 60.90% H, 3.83% Found: C,60.71% H, 3.87%.

EXAMPLE 1e

5,7-Dichloro-1-naphthalenecarboxylic Acid (V, R³ =5-Cl, R⁴ =7-Cl and R⁵=H)

Sulfuryl chloride (36.8 g, 273 mmoles) was added dropwise to a stirredsuspension of benz[c,d]indole-2(1H)-one (20 g, 119 mmoles) in glacialacetic acid (275 ml) at 20° to 22° C. The mixture was heated at refluxfor 1.5 hr, cooled and filtered. The collected solid was washed withglacial acetic acid and recrystallized from toluene to afford6,8-dichloro-benz[c,d]indole-2(1H)-one, mp 265° C., described by Y. T.Rozhinskii, Zhur. Org. Khim., 8, 2388 (1972). A mixture of the lattercompound (14 g, 58.8 mmoles) in 2% aqueous sodium hydroxide was refluxedfor 4 hr. The mixture was cooled, mixed with sodium nitrite (3.8 g, 55mmoles) and added dropwise to a cooled (0°-5° C.) solution ofconcentrated sulfuric acid (45 ml) in water (180 ml). The diazonium saltwas salted out by addition of sodium bromide, collected by filtrationand while still wet (drying dangerous) was added to a solution of sodiumhypophosphate (39.2 g of NaH₂ PO₂.H₂ O) in water (100 ml). The mixturewas stirred at 20°-22° C. for 48 hr. The resulting solid was collectedby filtration and suspended in saturated sodium bicarbonate (300 ml).The insoluble material was collected by filtration and resuspended inhot, saturated sodium bicarbonate (200 ml). The suspension was filteredand the filtrate was cooled. The resulting precipitate of the sodiumsalt of the product was collected by filtration. The free acid wasprepared by suspending the sodium salt in water and rendering thesuspension acidic. More product was obtained by acidification offiltrates of the sodium salt. The combined crops were recrystallizedfrom ethanol to yield 5.8 g of the title compound; mp 253°-254° C.; NMR(DMSO-d₆) δ 8.3 (m, 5H), 10.6 (broad, 1H), UVλmax (EtOH) 333 nm(ε2,350), 298 (7,000), 230 (53,300).

EXAMPLE 1f

5-Iodo-6-methoxy-1-naphthalenecarboxylic Acid (V, R³ =5-I, R⁴ =6-CH₃ Oand R⁵ =H)

Iodine (7.08 g) and iodic acid (2.78 g) were added to a stirred solutionof 6-methoxy-1-naphthalenecarboxylic acid methyl ester [15 g, 69.4mmoles, described by C. C. Price et al., J. Amer. Chem. Soc., 69, 2261(1947)] in 80% acetic acid (110 ml) and 98% sulfuric acid (0.97 ml). Thesolution was heated at 50° C. for 5 hr, cooled and poured into water(100 ml). After the addition of sodium bisulfite to destroy theunreacted iodine, the precipitate was collected, washed with water andrecrystallized from ethanol to afford the corresponding methyl ester ofthe title compound; mp 98°-99° C.; NMR (CDCl₃) δ 3.95 (s, 3H), 4.00 (s,3H), 8.00 (m, 5H). A mixture of the latter ester (7.1 g, 21 mmoles), 10%aqueous sodium hydroxide (35 ml) and methanol (19.5 ml) was heated atreflux for 1 hr. The solution was cooled to ice bath temperature andmade acidic with 1N aqueous hydrochloride. The resulting precipitate wascollected, washed with water and dried under reduced pressure overphosphorus pentoxide to give 7 g of the title compound; mp 259°-261° C.;NMR (DMSO-d₆) δ 4.0 (s, 3H), 8.15 (m, 5H), 10.56 (broad, 1H).

EXAMPLE 1g

5-Cyano-6-methoxy-1-naphthalenecarboxylic Acid (V, R³ =5-CN, R⁴ =6-CH₃ Oand R⁵ =H)

A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25ml) was added dropwise to a cooled suspension of6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.139 moles)in glacial acetic acid (2.75 ml). The precipitate was collected, washedwith water and crystallized from ethanol to give 33.3 g of5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.;NMR (CDCl₃) δ 3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4(m, 1H), 8.05 (d, J=6.75 Hz, 1H), 8.45 (d, J=8.25 Hz, 1H), 8.9 (d,J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu₂ (CN)₂.H₂ O(3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15drops of pyridine was heated at 180° C. for 5 hr. The hot mixture waspoured into a mixture of ice (50 g) and conc. NH₄ OH (50 ml). Theresulting precipitate was collected, washed with water, dried andrecrystallized from chloroform-ethyl acetate to afford 5.6 g of5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp210°-211° C., NMR (CDCl₃)δ 3.95 (s, 3H), 4.15 (s, 3H). To a stirredsolution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol(100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added.The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted withwater, cooled to 0° C. and rendered acidic with 1N aqueous HCl. Theprecipitate was collected and dried to yield 5.6 g of the titlecompound; mp>290° C.; NMR DMSO-d₆) δ 4.1 (s, 3H), 8.1 (m, 5H).

EXAMPLE 1h

5-(Trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic Acid (V, R³=5-CF₃, R⁴ =6-CH₃ O and R⁵ =H)

A mixture of 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester(10.26 g, 30 mmoles, described in Example 1f), trifluoromethyl iodide(12 g, 61.2 mmoles), freshly prepared copper powder (5.7 g, preparedaccording to the procedure of R. Q. Brewster and T. Groening, "OrganicSynthesis", Coll. Vo. II, John Wiley and Sons, New York, N.Y., U.S.A.,1948, p. 445) and pyridine (45 ml) was charged into a stainless steelautoclave. The vessel was shaken and heated at 120° C. for 20 hr andcooled to room temperature. The mixture was diluted with diethylether-ethyl acetate (1:1). The insoluble material was removed byfiltration. The filtrate was washed with 1N aqueous HCl, water and dried(MgSO₄). The solvent was removed under reduced pressure. The residue wascrystallized from ethanol to give 6.4 g of5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid methyl ester;mp 79°-80° C.; NMR (CDCl₃) δ 3.95 (s, 6 H), 8.00 (m, 5H). A mixture ofthe latter ester (6.3 g, 22 mmoles), 1N aqueous NaOH solution (34.12 ml)and methanol (100 ml) was stirred at 20°-22° C. for 4 hr. The mixturewas adjusted to pH 7 with 1N aqueous HCl, methanol was removed from themixture by distillation and the concentrated mixture was made acidic (pH2) with 1N aqueous HCl. The resulting precipitate was collected anddried to yield 6 g of the title compound; mp 218°-219° C.; NMR (DMSO-d₆)δ 4.0 (s, 3H), 8.3 (m, 5H), 10.6 (broad, 1H).

EXAMPLE 1i

5-Bromo-6-[3-trifluoromethyl)phenylmethoxy]-1-naphthalenecarboxylic Acid[V, R³ =5-Br, R⁴ =6-[(3-CF₃ -C₆ H₄)-CH₂ O] and R⁵ =H]

A mixture of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid (33.35 g,0.11 moles, described in example 1b) in glacial acetic acid (460 ml) and47% aqueous HBr(417 ml) was heated at reflux for 9 hr. The resultingprecipitate was collected, washed with water and dried over P₂ O₅ underreduced pressure. The precipitate was recrystallized from ethanol-waterto give 21.45 g of 5-bromo-6-hydroxy-1-naphthalenecarboxylic acid;mp>225° C.; NMR (DMSO-d₆) δ 8.0 (m, 5H), 11.0 (broad, 1H), 12.6 (broad,1H).

The latter acid (1.2 g, 4.5 mmoles) was suspended in drydimethylformamide (DMF, 25 ml). Sodium hydride (0.43 g, 9.0 mmoles, 50%mineral oil suspension) was added in small portions to the stirredsuspension. Stirring was continued until the evolution of hydrogenceased. A solution of 3-(trifluoromethyl)-phenylmethyl chloride (2.63 g,13.5 mmoles) in dry DMF (5 ml) was added dropwise and the mixture washeated to 50°-60° C. for 1 hr. The solvent was evaporated under reducedpressure to dryness. The residue was triturated with water. The solidwas separated from the water by filtration. The collected solid waswashed with hexane to remove residual mineral oil and thenrecrystallized from ethanolwater to give 1.7 g of5-bromo-6-[(3-trifluoromethyl)phenylmethoxy]-1-naphthalenecarboxylicacid, 3-trifluoromethyl ester; mp 114°-115° C., IR (CHCl₃) 1715 cm⁻¹.

A mixture of the latter ester (1.7 g, 2.9 mmoles), methanol (20 ml) and1N aqueous NaOH (4 ml) was stirred for 24 hr at 20°-22° C. Additional 1Naqueous NaOH was added and the mixture was stirred at 40° C. for 3 hr.The solvent was evaporated. The residue was dissolved in water and thesolution made acidic. The resulting precipitate was collected, washedwith water, dried and recrystallized from ethanol to give 1.0 g of thetitle compound; mp 229°-230° C.; NMR (DMSO-d₆) δ 5.5 (s, 2H), 8.1 (m,9H), 10.5 (broad, 1H).

5-Bromo-6-(4-chlorophenylmethoxy)-1-naphthalenecarboxylic acid, NMR(DMSO-d₆) δ 5.4 (s, 2H), 7.7 (m, 9H), 11.0 (broad, 1H), is obtained byfollowing the procedure of Example 1i but replacing3-(trifluoromethyl)phenylmethyl chloride with an equivalent amount of4-chlorophenylmethyl chloride.

EXAMPLE 1j

5-(Trifluoromethyl)-1-naphthalenecarboxylic Acid (V, R³ =5-CF₃ and R⁴and R⁵ =H)

A mixture of 5-iodo-1-naphthalenecarboxylic acid methyl ester [8.8 g, 28mmoles, described by C. Seer and R. School, Justus Leibigs Ann. Chem.,398, 82 (1913)], trifluoromethyl iodide (12 g, 61.2 mmoles), freshlyprepared copper powder (5.7 g, prepared according to the procedure of R.Q. Brewster and T. Groening, "Organic Syntheses", Coll. Vol. II, JohnWiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) and pyridine (45ml) was charged into a stainless steel autoclave. The vessel was shakenand heated at 130° C. for 24 hr and cooled to room temperature. Themixture was filtered to remove insoluble material. The filtrate waswashed with 1N aqueous HCl, water and brine, dried (MgSO₄) andconcentrated to dryness. The residue was crystallized from methanol togive 4.3 g of 5-(trifluoromethyl)-1-naphthalenecarboxylic acid methylester, NMR (CDCl₃) δ 4.0 (s, 3H), 8.0 (m, 6H).

The ester (4.25 g, 16.72 mmoles) was suspended in methanol (100 ml). A2N aqueous NaOH solution (16.72 ml, 2 equivalents) was added to thesuspension. The mixture was stirred at 20°-22° C. for 18 hr. Theresulting clear solution was adjusted to pH 8 with 1N aqueous HCl andconcentrated under reduced pressure. The concentrate was adjusted to pH3 with 1N aqueous HCl. The resulting precipitate was collected, washedwith water and dried under reduced pressure to give the title compound;mp 206°-208° C.

EXAMPLE 2

N-[(5-Bromo-1-naphthalenyl)carbonyl]-N-methylglycine Methyl Ester (II,R¹ and R=CH₃, R³ =5-Br and R⁴ and R⁵ =H)

Procedure A:

A catalytic amount (5 drops) of dry DMF was added to a suspension of thestarting material of formula V, 5-bromo-1-naphthalenecarboxylic acid ]10g, 39.8 mmoles, described by W. F. Short and H. Wang, J. Chem. Soc., 990(1950)], in thionyl chloride (100 ml). The suspension was heatedcautiously to reflux (caution: a vigorous reaction can occur). Themixture was refluxed for 20 min. The mixture was evaporated to dryness.Toluene was added to the solid residue and the mixture was evaporated todryness. The residue was dissolved in pyridine (100 ml). The solutionwas cooled in an ice bath. Dry N-methylglycine methyl esterhydrochloride (11.1 g, 79.6 mmoles), a starting material of formula VI,was added portionwise to the cooled solution. The mixture was stirredfor 2 hr at 20° C. and then heated at reflux for 1 hr. The pyridine wasremoved by evaporation. Water was added to the oily residue. The mixturewas extracted with ethyl acetate (3×150 ml). The combined extracts werewashed with 1N aqueous HCl solution, a saturated solution of sodiumbicarbonate and brine. After drying over MgSO₄, the extract was treatedwith charcoal, filtered and evaporated. The residue was crystallizedfrom diethyl ether or ethanol to give the title compound; mp 91°-92° C.;NMR (CDCl₃) δ 2.8 & 3.25 (2s, 3H), 3.6 & 3.85 (2s, 3H), 4.35 (broad,2H), 7.75 (m, 6H); UVλmax (EtOH) 321 nm (ε775), 316 (1,110), 299(6,660), 289 (9,250), 279 (7,400), 225 (66,600); Anal. Calcd; C, 53.59%H, 4.20% N, 4.17%; Found: C, 53.60% H, 4.27% N, 4.21%.

Procedure B:

A mixture of the starting material of formula V,5-bromo-1-naphthalenecarboxylic acid (12.8 g, 52 mmoles), and1-hydroxybenzotriazole (HOBt, 7.0 g, 52 mmoles) in DMF (200 ml) wasprepared. N,N'-dicyclohexylcarbodiimide (DCC, 10.6 g, 52 mmoles) in DMF(30 ml) was added to the mixture. The resulting mixture was stirred at20° C. for 1 hr and then cooled to 0° C. N-Methylglycine methyl esterhydrochloride (7.25 g, 52 mmoles) and then N-ethylmorpholine (6.7 ml, 52mmoles) were added to the cooled mixture. The mixture was stirred for 30min at 0° C. and then for 18 hr at 20° C. Thereafter, the mixture wasfiltered and concentrated to dryness under reduced pressure. The residuewas subjected to chromatography on 325 g of silica gel using ethylacetate-hexane (1:1) as the eluant. The pure fractions were pooled toyield 10.5 g of product which was recrystallized from ethyl acetate togive the title compound, identical to the product of procedure A of thisexample.

EXAMPLE 3

N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine Methyl Ester(I, R¹ and R² =CH₃, R³ =5-Br and R⁴ and R⁵ =H)

To a stirred solution ofN-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (35.5g, 106 mmoles, described in Example 2) in dry pyridine (100 ml),phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise. Themixture was stirred and refluxed for 1.5 hr and then poured into a literof water at 50° to 80° C. (caution: evolution of copious quantities ofH₂ S). The mixture was allowed to cool to 20° to 22° C. (roomtemperature), filtered and the filtrate was extracted with ethylacetate. The extract was washed with 1N aqueous HCl solution, brine, asaturated solution of sodium carbonate and brine, dried (MgSO₄),filtered and evaporated to dryness. The residue was recrystallized fromethanolwater (4:1) to give the title compound; mp 85°-86° C.; NMR(CDCl₃) δ 3.0 (s, 3H), 3.85 (s, 3H), 4.58 and 5.37 (2d, J=17, 2H),7.1-8.3 (m, 6H); UVλmax (EtOH) 281 nm (ε14,480), 218 (14,480).

By following serially the procedures of Examples 2 and 3 and using theappropriate starting material of formula V instead of5-bromo-1-naphthalenecarboxylic acid, other compounds of formula I inwhich R¹ and R² each is methyl are obtained. Examples of the lattercompounds are listed as products in Tables I and II together with theappropriate starting material of formula V used for their preparation.

                                      TABLE I                                     __________________________________________________________________________                         PRODUCT:N-[(prefix listed                                       STARTING MATERIAL                                                                           below-1-NAPHTHALENYL)-                                          OF FORMULA V (R.sup.5 = H)                                                                  THIOXOMETHYL]-N-METHYL-                                  EXAMPLE                                                                              R.sup.3                                                                            R.sup.4  GLYCINE METHYL ESTER                                     __________________________________________________________________________     4     4-Br H        4-bromo; NMR (CDCl.sub.3)δ                                              2.85 & 3.25(2s, 3H), 3.6 & 3.85                                               (2s, 3H), 4.35(m, 2H), 7.7(m,                                                 6H); IR (CHCl.sub.3)1730, 1620 cm.sup.-1                  5     8-Br H        8-bromo; IR(CHCl.sub.3)1730,                                                  1480, 1380, 1080 cm.sup.-1 ; NMR(CDCl.sub.3)δ                           3.0(s, 3H), 3.8(s, 3H), 3.65                                                  (m, 2H), 7.5(m, 6H)                                       6     5-CH.sub.3 O                                                                       H        5-methoxy; NMR(CDCl.sub.3)δ                                             2.81 & 3.21(2s, 3H), 3.58 &                                                   3.80(2s, 3H), 3.97(s, 3H), 4.37                                               (broad, 2H), 6.80(d, 1H), 7.40                                                (m, 4H), 8.27(m, 1H);IR (CHCl.sub.3)                                          1740, 1630, 1578 cm.sup.-1                                7     5-Me H        5-methyl; NMR(CDCl.sub.3)δ                                              2.68(s, 3H), 3.05(3H), 3.85                                                   (3H), 3.75 & 4.9(m, 2H), 7.6                                                  (s, 6H)                                                   8     5-Br 6-[CH.sub.3 (CH.sub.2).sub.4 O]                                                        5-bromo-6-pentyloxy; mp                                                       80-83° C.; NMR(CDCl.sub.3)δ                                      0.9(t, J = 7Hz, 3H), 1.1-2.0                                                  (broad, 2H), 3.0(s, 3H), 3.8                                                  (s, 3H), 4.1(m, 2H), 7.1-8.5(broad,                                           5H)                                                       9     5-CN H        5-cyano; NMR(CDCl.sub.3)δ                                               3.00(s, 3H), 3.85(s, 3H), 4.45                                                & 5.45(d, 2H), 7.18(m, 6H)                                9a    4-CN H        4-cyano; NMR(CDCl.sub.3)δ                                               3.1(s, 3H), 3.85(s, 3H), 4.55                                                 & 5.25(2d, J = 17Hz, 2H), 7.0-                                                8.4(m, 6H)                                               10     5-NO.sub.2                                                                         H        5-nitro; mp 116-117° C.                           11     5-Cl H        5-chloro; mass spectrum,                                                      m/e: 307/309(M.sup.+), 274/276                                                (M.sup.+  --H, S), 248/246(M.sup.+  --COOMe)             12     5-Br 6-CH.sub.3 O                                                                           5-bromo-6-methoxy; mp                                                         115-117° C.; NMR(CDCl.sub.3)δ                                    3.00(s, 3H), 3.84(s, 3H), 3.98                                                (s, 3H)                                                  13     5-Br 6-CH.sub.3                                                                             5-bromo-6-methyl; NMR                                                         (CDCl.sub.3)δ 2.6(s, 3H), 3.0(s,                                        3H), 3.85(s, 3H), 4.5 & 5.35                                                  (d, J = 16.5Hz, 2H), 7.7(m, 5H)                          14     H    H        *; IR(CHCl.sub.3) 1735 cm.sup.-1                         15     4-Cl H        4-chloro; mp 100-101° C.;                                              NMR(CDCl.sub.3)δ 3.10 & 3.62                                            (2s, 3H); 3.90 & 3.70(2s, 3H)                                                 4.04, 4.55 & 5.37(s, 2d, J =                                                  16Hz, 2H), 7.2-8.4(m, 6H);                                                    IR(CHCl.sub.3) 1740 cm.sup.-1 ; UVλmax                                 (EtOH) 283 nm (ε7,100), 219                                           (52,000); Anal. Calcd: C, 58.54%                                              H, 4.58% N, 4.55%; Found:                                                     C, 58.58% H, 4.76% N, 4.58%                              16     3-Cl 4-CH.sub.3 O                                                                           3-chloro-4-methoxy; mp                                                        85-86° C.; NMR(CDCl.sub.3)δ 3.05                                 (s, 3H), 3.85(s, 3H), 4.00(s, 3H),                                            4.58 & 5.3(2d, J = 17Hz, 2H),                                                 7.6(m, 5H)                                               17     5-Cl 7-Cl     5,7-dichloro; m/e; 325/327/                                                   329(M.sup.+), 266, 268, 270(M.sup.+  --                                       COOCH.sub.3), 223/225/227(M.sup.+  --                                         CH.sub.3 --N--CH.sub.2 --COOCH.sub.3)                    18     5-I  6-CH.sub.3 O                                                                           5-iodo-6-methoxy; mp 149-                                                     150° C.; NMR(CDCl.sub.3) δ 3.00                                  (s, 3H), 3.85(s, 3H), 3.95(s,                                                 3H), 4.4 & 5.45(d, 2H), 7.6                                                   (m, 5H)                                                  19     5-CN 6-CH.sub.3 O                                                                           5-cyano-6-methoxy; mp                                                         164-165° C.; NMR(CDCl.sub.3)δ                                    3.05(s, 3H), 3.90(s, 3H), 4.07                                                (s, 3H), 4.35 & 5.55(d, J = 16.8Hz,                                           2H), 7.80(m, 5H)                                         __________________________________________________________________________     *No prefix as compound is N((1-naphthalenyl)thioxomethyl)-N-methylglycine     methyl ester                                                             

With reference to Table I, the starting materials of formula V aredescribed by T. L. Jacobs, et al., J. Org. Chem., II, 27 (1946) forexample 4; by H. G. Rule et al., J. Chem. Soc., 168 (1934) for example5; by A. Girardet and N. Lorusso, Helv. Chim. Acta., 49, 471 (1966) forexample 6; by M. J. S. Dewar and P. J. Grisdale, J. Am. Chem. Soc., 84,3541 (1962) for example 7; in example 1c for example 8; by M. J. S.Dewar and P. J. Grisdale, J. Am. Chem. Soc., 84, 3541 (1962) forexamples 9, 9a, 10 and 11; in example 1b for example 12; in example 1cfor example 13; by H. Gilman et al., "Organic Syntheses", Coll. Vol. II,John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 425 for example14; by T. L. Jacobs et al., J. Org. Chem., II 27 (1946) for example 15;in example 1d for example 16; in example 1e for example 17; in example1f for example 18; and in example 1g for example 19.

                                      TABLE II                                    __________________________________________________________________________                             PRODUCT: N-[[prefix listed                                  STARTING MATERIAL below-1-NAPHTHALENYL]-                                      OF FORMULA V(R.sup.5 = H)                                                                       THIOXOMETHYL]-N-METHYL-                              EXAMPLE                                                                              R.sup.3  R.sup.4  GLYCINE METHYL ESTER                                 __________________________________________________________________________    20     5-Br     6-[CH.sub.3 O(CH.sub.2).sub.3 O]                                                       5-bromo-6-(3-methoxypro-                                                      poxy); NMR(CDCl.sub.3) δ 2.1(m,                                         4H), 3.35(s, 6H), 3.55(m, 4H),                                                4.25(t, J = 6Hz, 2H), 4.45(t,                                                 5 = 6Hz, 2H), 7.4(m, 2H), 8.0                                                 (d, J = 8Hz, 1H), 8.4(d, J =                                                  8Hz, 1H), 8.85(d, J = 8Hz, 1H)                       21     5-[CH.sub.2 ═C(CH.sub.3)]                                                          H        5-(1-methylethenyl); mp 93-95° C.;                                     NMR(CDCl.sub.3) δ 2.15(s, 3H),                                          3.05(s, 3H), 3.85(s, 3H), 4.55                                                & 5.3(2s, 2H), 5.0 & 5.35(2s,                                                 2H), 7.6(m, 6H)                                      22     5-[(CH.sub.3).sub.2 CH]                                                                H        5-(1-methylethyl); NMR                                                        (CDCl.sub.3) δ 1.35(m, 6H), 3.0                                         & 3.55(2s, 3H), 3.65 & 3.85                                                   (2s, 3H), 4.95(2H), 7.5(m, 6H)                       23     5-CF.sub.3                                                                             6-CH.sub.3 O                                                                           5-(trifluoromethyl)-6-methoxy;                                                mp 109-110° C.; NMR(CDCl.sub.3)δ                                 3.00(s, 3H), 3.85(s, 3H), 3.95                                                (s, 3H), 4.35 & 5.45(d, 2H),                                                  7.7(m, 5H)                                           24     5-Br     6-[(3-CF.sub.3 --C.sub.6 H.sub.4)-                                                     5-bromo-6-[3-(trifluoromethyl)-                                      CH.sub.2 O]                                                                            phenylmethoxy]; NMR(CDCl.sub.3)                                               δ 3.00(s, 3H), 3.85(s, 3H),                                             4.4 & 5.4(2d, J = 16.5Hz, 2H),                                                5.25(s, 2H), 7.6(m, 9H)                               24a   5-Br     6-[(4-Cl--C.sub.6 H.sub.4)-                                                            5-bromo-6-(4-chlorophenyl-                                           CH.sub.2 O]                                                                            methoxy); NMR(CDCl.sub.3) δ                                             3.00(s, 3H), 3.85(s, 3H), 4.40                                                & 5.40(d, 2H), 5.2(s, 2H), 7.5                                                m 9H)                                                 24b   5-CF.sub.3                                                                             H        5-(trifluoromethyl); NMR                                                      (CDCl.sub.3) δ 3.00(s, 3H), 3.85                                        (s, 3H), 4.5 & 5.4(d, 2H), 7.2-                                               8.3(m, 6H).                                          __________________________________________________________________________

With reference to Table II, the starting materials of formula V aredescribed in example 1i, herein, for example 20; in example 1 forexample 21; in example 1a for example 22; in example 1h for example 23;in example 1i for example 24 and example 24a; and in example 1j forexample 24b.

By following serially the procedures of examples 2 and 3, but using theappropriate starting material of formula VI instead of N-methylglycine,other compounds of formula I in which R² is lower alkyl, R³ is 5-bromo,R⁴ is hydrogen are obtained. Examples of the latter compounds are listedas products in Table III together with the appropriate starting materialof formula VI used for their preparation.

                                      TABLE III                                   __________________________________________________________________________                        PRODUCT: N-[(5-BROMO-1-                                          STARTING MATERIAL                                                                          NAPHTHALENYL)THIOXO-                                             OF FORMULA VI                                                                              METHYL]-suffix listed                                     EXAMPLE                                                                              R.sup.1  R   below                                                     __________________________________________________________________________    25     H        CH.sub.3                                                                          glycine methyl ester; mp 126-                                                 130° C.; NMR(CDCl.sub.3) δ 3.8                                   (s, 3H), 4.6(d, J = 7Hz, 2H),                                                 7.15-8.15(m, 6H)                                          26     n-C.sub.3 H.sub.7                                                                      C.sub.2 H.sub.5                                                                   N-propylglycine ethyl ester;                                                  NMR(CDCl.sub.3) δ 0.65(t, J =                                           7Hz, 3H), 1.4(t, 3H), 1.45(m,                                                 2H), 3.2(t, J = 7Hz, 2H), 4.3                                                 (q, J = 7Hz, 2H), 4.35(d, J =                                                 17Hz, 1H), 5.3(d, J = 17Hz, 1H),                                              7.7(m, 6H); IR(CHCl.sub.3) 1740 cm.sup.-1                 27     CH.sub.2 ═CH--CH.sub.2                                                             CH.sub.3                                                                          N-(2-propenyl)glycine methyl                                                  ester; mp 72-74° C.                                28     C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          N-ethylglycine methyl ester;                                                  NMR(CDCl.sub.3) δ 1.10(t, 3H),                                          3.35(q, 2H), 3.85(s, 3H), 4.40 &                                              5.25(d, 2H), 7.6(m, 6H)                                   29     n-C.sub.4 H.sub.9                                                                      C.sub.2 H.sub.5                                                                   N-butylglycine ethyl ester;                                                   NMR(CDCl.sub.3) δ 0.65(t, J =                                           5.5 Hz, 3H), 1.0(m, 2H), 1.38                                                 (t, 3H), 1.40(m, 2H), 3.25(m,                                                 2H), 4.25 & 5.30(d, J = 16Hz,                                                 2H), 7.7(m, 6H)                                           30     C.sub.6 H.sub.5 CH.sub.2                                                               C.sub.2 H.sub.5                                                                   N-(phenylmethyl)glycine ethyl                                                 ester; mp 141-142° C.; NMR(CDCl.sub.3)                                 δ 1.35(t, J = 7Hz, 3H), 4.50                                            (m, 6H), 7.50(m, 11H); IR(Nujol*)                                             1743 cm.sup.-1                                            __________________________________________________________________________

EXAMPLE 31

By following serially the procedure of Examples 2 and 3, but using theappropriate starting material of formula V and the appropriate aminoacidester of formula VI, still other compounds of formula I in which R² islower alkyl are obtained. For example, by using3-chloro-4-methoxy-1-naphthalenecarboxylic acid, described in Example1d, as the starting material of formula V, and using glycine ethyl esterhydrochloride as the starting material of formula VI,N-[(3-chloro-4-methoxy-1-naphthalenyl)thioxomethyl]glycine ethyl ester;IR (CHCl₃) 3420, 3340, 1740, 1665 cm⁻¹ ; viaN-[(3-chloro-4-methoxy-1-naphthalenyl)carbonyl]glycine ethyl ester; mp140°-141° C.; NMR (CDCl₃) δ 1.3 (t, J=7 Hz, 3H), 4.2 (m, 4H), 6.55(broad, 1H), 7.55 (m, 3H), 8.2 (m, 2H), was obtained.

EXAMPLE 32

N-[(5-Bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine (I, R¹ =CH₃,R², R⁴ and R⁵ =H and R³ =5-Br) * Trademark

A 1N aqueous NaOH solution (25 ml) was added to a suspension ofN-[(5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester(7.3 g, 20.7 mmoles; described in Example 3) in methanol (75 ml). Themixture was stirred at 20° to 22° C. for 21/2 hr, neutralized to pH 7with aqueous HCl and concentrated under reduced pressure to removemethanol. The residual solution was rendered acidic (pH=2) with theaddition of aqueous HCl solution and extracted with ethyl acetate. Theextract was dried (MgSO₄) and evaporated to dryness. The residue wascrystallized from ethyl acetate-hexane to give 5.3 g of the titlecompound; mp 181° C.; NMR(DMSO-d₆) δ2.95 (s,3H), 4.65 and 5.2 (2d,J=16.8, 2H), 7.85 (m,6H), UVλmax (EtOH) 285 nm (ε12,300), 280 (12,400),221 (42,600); IR(Nujol *) 2900, 1720 cm⁻¹ ; Anal Calcd: C, 49.72% H,3.58% N, 4.14%; Found: C, 49.63% H, 3.63% N, 4.18%.

In the same manner, but replacingN-[(5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl esterwith an equivalent amount ofN-[(3-chloro-4-methoxy-1-naphthalenyl)thioxomethyl]glycine ethyl ester,described in Example 31,N-[(3-chloro-4-methoxy-1-naphthalenyl)thioxomethyl]glycine [mp 217° C.(dec); NMR(DMSO-d₆) δ3.96 (s, 3H), 4.42 (d, J=6 Hz, 2H), 7.40 (s, 1H),7.65 (m, 2H), 8.18 (m, 2H); IR (Nujol *) 3150, 2900, 1720, 1140 cm⁻¹ ;UVλmax (EtOH) 277 nm (ε11,400), 224 (51,300); Anal Calcd: C, 54.28% H,3.91% N, 4.52%; Found: C, 54.26% H, 4.06% N, 4.62%] was obtained.

By following the procedure of Example 32, but replacingN-[(5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl esterwith an equivalent amount of another ester compound of formula I inwhich R² is lower alkyl, or corresponding compounds in which R isar(lower)alkyl, the a corresponding compound of formula III of formula Iin which R² is hydrogen was obtained. Examples of the latter compoundsare listed as products in Tables IV, V and VI together with a notationto the corresponding compound of formula I in which R² is lower alkylfrom which they are prepared. In each case the compound of formula I inwhich R² is lower alkyl, the starting material, is noted by the examplein which it was prepared.

                                      TABLE IV                                    __________________________________________________________________________                             PRODUCT: N-[(prefix listed                                  NO. OF THE EXAMPLE IN                                                                           below-1-NAPHTHALENYL)-                                      WHICH STARTING MATERIAL                                                                         THIOXOMETHYL]-N-METHYL-                              EXAMPLE                                                                              WAS PREPARED      GLYCINE                                              __________________________________________________________________________    33      4                4-bromo; mp 168-169° C.,                                               NMR(DMSO-d.sub.6) δ 3.0(s, 3H),                                         4.65 & 5.15(d, J = 16.5Hz, 2H),                                               7.7(m, 6H); Anal Calcd: C,                                                    49.71% H, 3.58% N, 4.14%;                                                     Found: C, 49.56% H, 3.42%                                                     N, 4.22%                                             34      5                8-bromo; mp 65-85° C.;                                                 Anal Calcd: C, 49.72% H,                                                      3.58% N, 4.14%, Found: C,                                                     53.54% H, 4.05% N, 4.40%                             35      6                5-methoxy; mp 120° C.;                                                 NMR(DMSO-d.sub.6) δ 2.93(s,                                             3H), 3.90(s, 3H), 4.65& 5.16                                                  (2d, J = 17Hz, 2H), 6.95(2d,                                                  J.sub.1 = 7Hz, J.sub.2 = 3Hz, 1H), 7.35                                       (m, 4H), 8.11(2d, J.sub.1 = 8Hz,                                              J.sub.2 = 2Hz, 1H); IR(Nujol*)                                                2900, 1734, 1715 cm.sup.-1 ; UVλmax                                    EtOH) 281 nm(ε 11,600), 233                                           (30,600); Anal Calcd: C, 62.27%                                               H, 5.23% N, 4.84%; Found:                                                     C, 61.62% H, 5.95% N, 4.22%                          36      7                5-methyl; mp 190-191° C.,                                              NMR(CDCl.sub.3) δ 2.66(s, 3H),                                          3.05(s, 3H), 3.85 & 5.0(m,                                                    2H), 7.5(m, 6H), 8.75(broad,                                                  1H); IR(CHCl.sub.3) 3000, 1755                                                1720 cm.sup.-1 ; UVλmax(EtOH)                                          282 nm(ε 15,280), 226(39,690),                                        218(41,385); Anal Calcd: C,                                                   65.90% H, 5.53% N, 5.12%;                                                     Found: C, 65.79% H, 5.57%                                                     N, 5.08%                                             37      8                5-bromo-6-pentyloxy;                                                          mp 211-217° C.; NMR(DMSO-d.sub.6)                                      δ                                                                       0.9(t, J = 6Hz, 3H), 1.6(m,                                                   2H), 2.9(s, 3H), 4.2(t, J =                                                   6Hz, 2H), 3.95 & 5.15(d, J                                                    = 15Hz, 2H), 7.1-8.55(m, 5H);                                                 IR(Nujol*) 3000, 1650 cm.sup.-1                      38      9                5-cyano; mp 190-200° C.;                                               NMR(DMSO-d.sub.6) δ 3.00(s,                                             3H), 4.65 & 5.15(d, J = 17Hz,                                                 2H), 7.95(m, 6H); IR(Nujol*)                                                  3000, 2230, 1730 cm.sup.-1 ; UVλmax                                    (EtOH) 313 nm(ε 5,600), 271                                           (13,850), 249(14,620), 222(48,340);                                           Anal Calcd: C, 63.36% H,                                                      4.34% N, 9.85%; Found: C,                                                     62.01% H, 4.34% N, 9.36%                             38a     9a               4-cyano; mp 192-193° C.; NMR                                           (DMSO-d.sub.6) δ 3.0(s, 3H), 4.7                                        & 5.2(d, J = 17Hz, 2H), 7.8                                                   (m, 6H), 10.05(broad, 1H);                                                    IR(Nujol*) 3180, 2230, 1745                                                   (with inflection at 1755)cm .sup.-1                  39     10                5-nitro; mp 142-143° C.;                                               NMR(CDCl.sub.3) δ 3.05(s, 3H),                                          4.65 & 5.4(d, 2H), 7.9(m,                                                     6H), 9.4(broad, 1H); IR(Nujol*)                                               2900, 1715, 1530, 1345 cm.sup.-1                                              UVλmax(EtOH) 332 nm(ε 4,110)                                   269(17,010); Anal Calcd: C,                                                   55.26% H, 3.96% N, 9.20%;                                                     Found: C, 55.17% H, 3.86%                                                     N, 9.10%                                             40     11                5-chloro; mp 153-154° C.;                                              NMR(CDCl.sub.3) δ 3.03(s, 3H),                                          4.67 & 5.33(d, J = 17Hz, 2H),                                                 7.50(m, 4H), 7.90(d, J =  8Hz,                                                1H), 8.25(d, J = 8, 1H); IR(CHCl.sub.3)                                       3000, 1720 cm.sup.-1 ; UVλmax                                          (EtOH) 280 nm(ε 16,780),                                              212(52,290); Anal Calcd: C,                                                   57.23% H, 4.12% N, 4.77%;                                                     Found: C, 58.02% H, 4.28%                                                     N, 4.94%                                             41     12                5-bromo-6-methoxy; mp                                                         166-168° C.; NMR(CDCl.sub.3) δ                                   3.02                                                                          (s, 3H), 4.06(s, 3H), 4.61 &                                                  5.39(d, J = 17Hz, 2H); IR(CHCl.sub.3)                                         3000, 1718 cm.sup.-1 ; UVλmax                                          (EtOH)341 nm(4,350), 329                                                      (4,015), 273(13,150), 237(51,260);                                            Anal Calcd: C, 48.92% H,                                                      3.83% N, 3.80%; Found: C,                                                     49.11% H, 3.90% N, 3.91%                             42     13                5-bromo-6-methyl; mp                                                          190-192° C.; NMR(CDCl.sub.3) δ                                   2.6(s, 3H), 3.05(s, 3H), 4.56                                                 & 5.3(d, 2H), 7.6(m, 5H);                                                     IR(CHCl.sub.3) 3000, 1720 cm.sup.-1                                           UVλmax(EtOH) 280 nm (ε                                         14,055), 223(43,400); Anal                                                    Calcd: C, 51,14% H, 4.01%                                                     N, 3.98%; Found: C, 51.21%                                                    H, 4.03% N, 4.00%                                    43     14                **; mp 146-147° C.; NMR(CDCl.sub.3)                                    δ 3.05 & 3.70(2s, 3H), 4.07,                                            4.75 & 5.30(s, 2d, J = 17Hz,                                                  2H), 6.8-8.0(m, 7H), 9.20                                                     (broad, 1H); IR(CHCl.sub.3) 3000,                                             1720(inflection at 1755)cm.sup.-1 ;                                           UVλmax(EtOH) 280 nm(ε                                          14,415), 215(53,450); Anal Calcd:                                             C, 64.87% H, 5.05% N, 5.40%;                                                  Found: C, 64.89% H, 5.14%                                                     N, 5.51%                                             44     15                4-chloro; mp 165-166° C.;                                              NMR(CDCl.sub.3) δ 3.05 & 3.70(2s,                                       3H), 4.10, 4.70 & 5.3(s, 2d,                                                  J = 17Hz, 2H), 7.2-8.4(m,                                                     6H), 10.5(s, 1H), IR(CHCl.sub.3)                                              3000, 1725(with inflection                                                    at 1765)cm.sup.-1 ; UVλmax(EtOH)                                       283 nm(ε 13,500), 220(49,600);                                        Anal Calcd: C, 57.24% H,                                                      4.12% N, 4.77%; Found: C,                                                     57.56% H, 4.28% N, 4.84%                             45     16                3-chloro-4-methoxy; mp                                                        138-139° C.; NMR(DMSO-d.sub.6)                                         δ 3.0(s, 3H), 3.45(s, 3H),                                              4.6 & 5.15(2d, J =  16.8Hz,                                                   2H), 7.3(s, 1H), 7.8(m, 4H);                                                  IR(Nujol*) 2900, 1723 cm.sup.-1 ;                                             UVλmax(EtOH) 329 nm(ε                                          2,200), 282(13,210), 224(53,980);                                             Anal Calcd: C, 55.64% H,                                                      4.36% N, 4.33%; Found: C,                                                     55.63% H, 4.48% N, 4.40%                             46     17                5,7-dichloro; mp174-175° C.;                                           NMR(DMSO-d.sub.6) δ 2.97(3H),                                           4.57 & 5.27(2d, J = 17Hz,                                                     2H), 7.3-8.3(m, 5H); IR(Nujol*)                                               3000, 1708 cm.sup.-1 ; UVλmax                                          (EtOH) 334 nm(ε 3,050), 273                                           (15,810), 226(63,800); Anal                                                   Calcd: C, 51.23% H, 3.38%                                                     N, 4.27%; Found: C, 51.44%                                                    H, 3.52% N, 4.40%                                    47     18                5-iodo-6-methoxy; mp                                                          161-163° C.; NMR(DMSO-d.sub.6)                                         δ 2.95(s, 3H), 3.95(s, 3H),                                             4.6 & 5.2(d, J = 17Hz, 2H),                                                   7.5(m, 5H); IR(Nujol*) 2900,                                                  1720 cm.sup.-1 ; UVλmax(EtOH)                                          343 nm(ε 7,900), 333(7,250)                                           308(12,400), 273(20,500),                                                     240(74,200); Anal Calcd: C,                                                   43.39% H, 3.40% N, 3.37%;                                                     Found: C, 42.75% H, 3.35%                                                     N, 3.37%                                             48     19                5-cyano-6-methoxy; mp                                                         155-157° C.; NMR(CDCl.sub.3) δ                                   3.05(s, 3H), 4.05(s, 3H), 4.55                                                & 5.45(d, J = 17Hz, 2H), 7.7                                                  (m, 5H); IR(CHCl.sub.3) 2900, 2220,                                           1725 cm.sup.-1 ; UVλmax(EtOH)                                          346 nm(ε 5,600), 339(5,500),                                          232(46,500)                                          __________________________________________________________________________     *Trademark                                                                    **No prefix as compound is N((1-naphthalenyl)thioxomethyl)-N-methylglycin

                                      TABLE V                                     __________________________________________________________________________                             PRODUCT: N-[[prefix listed                                  NO. OF THE EXAMPLE IN                                                                           below-1-NAPHTHALENYL]-                                      WHICH STARTING MATERIAL                                                                         THIOXOMETHYL]-N-METHYL-                              EXAMPLE                                                                              WAS PREPARED      GLYCINE                                              __________________________________________________________________________    49     20                5-bromo-6-(3-methoxy-pro-                                                     poxy); NMR(CDCl.sub.3) δ 2.1(q,                                         J = 6Hz, 2H), 3.0(s, 3H), 3.35                                                (s, 3H), 3.65(t, J = 6Hz, 2H),                                                4.25(t, J = 6Hz, 2H), 4.55                                                    (d, J = 16Hz, 1H), 5.4(d, J                                                   = 16Hz, 1H), 7.4(m, 3H), 7.95                                                 (d, J = 8Hz, 1H), 8.2(d, J =                                                  8Hz, 1H); IR(CHCl.sub.3) 2900,                                                1720 cm.sup.-1 ; UVλmax(EtOH)                                          341 nm(ε 3,920), 330(3,730),                                          238(49,400); Anal Calcd: C,                                                   50.69% H, 4.73% N, 3.29%;                                                     Found: C, 50.29% H, 4.89%                                                     N, 3.23%                                             50     21                5-(1-methylethenyl); mp                                                       146-148° C.; NMR(CDCl.sub.3) δ                                   2.2(s, 3H), 3.1(s, 3H), 4.75                                                  & 5.35(d, 2H), 5.05 & 5.4                                                     (d, 2H), 7.6(m, 6H), 8.5(broad,                                               1H); IR(CHCl.sub.3) 2900, 1760,                                               1720 cm.sup.-1 ; UVλmax(EtOH)                                          282 nm(ε 14,000), 216(38,900);                                        Anal Calcd: C, 68.20% H,                                                      5.72% N, 4.68%; C, 69.06%                                                     H, 6.03% N, 4.39%                                    51     22                5-(1-methylethyl); mp                                                         136-136° C.; NMR(CDCl.sub.3) δ                                   1.40(m, 6H), 3.05 & 3.65(d,                                                   3H), 3.65(m, 1H), 5.05(m,                                                     2H), 7.5(m, 6H), 9.60(broad,                                                  1H); IR(CHCl.sub.3) 2900, 1755,                                               1720 cm.sup.-1 ; Anal Calcd: C,                                               67.74% H, 6.35% N, 4.65%;                                                     Found: C, 66.44% H, 6.56%                                                     N, 4.16%                                             52     23                5-(trifluoromethyl)-6-methoxy;                                                mp 164-165° C.; NMR(CDCl.sub.3)                                        δ 3.05(s, 3H), 3.95(s, 3H),                                             4.55 & 5.4(d, J = 17Hz, 2H),                                                  7.6(m, 5H), 9.8(broad, 1H);                                                   IR(CHCl.sub.3) 2900, 1720 cm.sup.-1 ;                                         UVλmax(EtOH) 337 nm(ε 3,895),                                  268(13,260), 226(49,315); Anal                                                Calcd: C, 53.78% H, 3.95%                                                     N, 3.92%; Found: C, 53.56%                                                    H, 3.95% N, 3.87%                                    53     24                5-bromo-6-(3-trifluoromethyl)-                                                phenylmethoxy]; mp 125° C.;                                            NMR(DMSO-d.sub.6) δ 3.0(s,                                              3H), 4.65 & 5.25(2d, J = 17Hz,                                                2H), 5.5(s, 2H), 7.8(m, 9H);                                                  IR(Nujol*) 2900, 1720 cm.sup.-1 ;                                             UMλmax(EtOH) 340 nm(ε 3,950),                                  270(13,900), 263(14,200), 238                                                 (54,200); Anal Calcd C, 51.57%                                                H, 3.35% N, 2.73% Found:                                                      C, 52.11% H, 3.22% N,2.94%                           53a     24a              5-bromo-6-(4-chlorophenyl-                                                    methoxy); mp 88-90° C. (dec);                                          NMR(DMSO-d.sub.6) δ2.95(s,                                              3H), 4.63 & 5.20(d, J = 17.25Hz,                                              2H), 5.4(s, 2H), 7.6(m, 9H);                                                  IR(CHCl.sub.3) 3000, 1720 cm.sup.-1 ;                                         UVλmax(EtOH) 340 nm(ε 3,495),                                  326(3,450), 238(53,480)                              53b     24b              (5-trifluoromethyl); mp                                                       156-158° C.; NMR(CDCl.sub.3) δ                                   3.05(s, 3H), 4.65 & 5.4(d,                                                    J = 17Hz, 2H), 7.85(m, 6H),                                                   10.4(b, 1H); IR(CHCl.sub.3) 2900,                                             1720(with inflection at 1755),                                                1305 cm.sup.-1 ; UVλmax(EtOH)                                          278 nm(ε 12,900), 216(68,800);                                        Anal Calcd: C, 55.03% H,                                                      3.70% N, 4.27% Found: C,                                                      54.69% H, 3.70% N, 4.27%                             __________________________________________________________________________     *Trademark                                                               

                                      TABLE VI                                    __________________________________________________________________________                             PRODUCT: N-[(5-BROMO-1-                                     NO. OF THE EXAMPLE IN                                                                           NAPHTHALENYL)THIOXO-                                        WHICH STARTING MATERIAL                                                                         METHYL]-suffix listed                                EXAMPLE                                                                              WAS PREPARED      below                                                __________________________________________________________________________    54     25                glycine; mp 232-237° C.; NMR                                           (DMSO-d.sub.6) δ 4.5(d, J = 5.5,                                        2H), 7.8(m, 6H), 10.8(broad,                                                  1H); IR(Nujol*) 3200, 1720;                                                   UVλmax(EtOH) 275 nm(ε                                          11,700), 217(44,800); Anal Calcd                                              C, 48.15% H, 3.10% N, 4.30%;                                                  Found: C, 48.65% H, 3.18%                                                     N, 4.37%                                             55     26                N-propylglycine; NMR(CDCl.sub.3)                                              δ 0.65(t, J = 8Hz, 3H), 1.55                                            (sextet, J = 8Hz, 2H), 3.25                                                   (t, J = 8Hz, 3H), 4.55(d, J                                                   = 17Hz, 1H), 5.3(d, J = 17Hz,                                                 1H), 7.7(m, 6H); IR(CHCl.sub.3)                                               2900, 1723 cm.sup.-1 ; UVλmax                                          (EtOH) 277 nm(ε 14,800), 216                                          (61,200); Anal Calcd: C, 52.44%                                               H, 4.41% N, 3.83%; Found:                                                     C, 52.53% H, 4.44% N, 3.73%                          56     27                N-(2-propylene)glycine: NMR                                                   (CDCl.sub.3) δ 3.5(m, 2H), 3.9                                          (m, 2H), 5.4(m, 3H), 6.95                                                     (m, 1H), 7.2-8.4(m, 6H); IR                                                   (CHCl.sub.3) 2900, 1720 with inflection                                       at 1760 cm.sup.-1 ; UVλmax(EtOH)                                       277 nm(ε 14,400), 219(39,700);                                        Anal Calcd: C, 52.76% H,                                                      3.87% N, 3.84%; Found: C,                                                     52.93% H, 4.28% N, 3.68%                             57     28                N-ethylglycine; mp 182-184° C.;                                        NMR(DMSO-d.sub.6) δ 0.95(t,                                             J = 7Hz, 3H), 3.25(q, J = 7Hz,                                                2H), 4.58 & 5.05(d, J = 16.5Hz,                                               2H), 7.7(m, 6H); IR(Nujol*)                                                   2900, 1720 cm.sup.-1 ; UVλmax                                          (EtOH) 276 nm(ε 14,795),                                              219(42,305); Anal Calcd: C,                                                   51.14% H, 4.00% N, 3.97%;                                                     Found: C, 51.33% H, 4.08%                                                     N, 4.05%                                             58     29                N-butylglycine; mp 65-68° C.                                           (dec); NMR(CDCl.sub.3) δ                                                0.63(t, J = 5.5Hz, 3H), 1.2                                                   (m, 4H), 3.25(t, J = 7.5Hz,                                                   2H), 4.5 & 5.3(d, J = 16.8Hz,                                                 2H), 6.9(broad, 1H), 7.7(m,                                                   6H); IR(CHCl.sub.3) 2900, 1720 cm.sup.-1 ;                                    UVλmax(EtOH) 378 nm(ε                                          13,900), 219(42,000)                                 59     30                N-(phenylmethyl)glycine; mp                                                   98° C. (decomp); NMR(CDCl.sub.3) δ                               4.5 & 5.35(d, 2H), 4.45(m,                                                    2H), 7.6(m, 11H); IR(Nujol*)                                                  2900, 1710 cm.sup.-1 ; UVλmax                                          (EtOH) 278 nm(15,620), 219                                                    (43,465); Anal Calcd: C, 58.01%                                               H, 3.94% N, 3.35%: Found:                                                     C, 58.29% H, 4.27% N, 3.24%                          __________________________________________________________________________     *Trademark                                                               

EXAMPLE 60

N-[(5-Bromo-1-naphthalenyl)carbonyl]-N-methylglycine (IV, R¹ =CH₃, R³=5-Br and R⁴ and R⁵ =H)

N-[(5-Bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (3.7g, 11.0 mmoles, described in Example 2) was suspended in methanol (50ml). A solution of 1N aqueous NaOH (13.2 ml) was added to thesuspension. The mixture was stirred at 20°-22° C. for 1.5 hr. Themixture was neutralized with aqueous HCl and concentrated under reducedpressure to remove the methanol. The residual solution was made acidicwith aqueous HCl and extracted with ethyl acetate. The extract was dried(MgSO₄), filtered and evaporated to dryness. The residue wascrystallized from ethanol-water to give 3.25 g of the title compound; mp205° C.; NMR(DMSO-d₆) δ2.75 and 3.10 (2s, 3H), 2.75 and 3.10 (2s, 3H),3.75 and 4.25 (2s, 2H), 7.3-8.3 (m, 6H); IR (Nujol *) 1745 withinflection at 1720, 1580 cm⁻¹ ; UVλmax (EtOH) 322 nm (ε680), 316(1,000), 299 (6,510), 289 (9,055), 279 (7,150) 226 (63,080); Anal Calcd:C, 52.19% H, 3.76% N, 4.35%; Found: C, 52.09% H, 38.4% N, 4.48%.

By following the procedure of example 60 but replacingN-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester withan equivalent amount of another ester compound of formula II in which Ris lower alkyl or ar(lower)alkyl, the corresponding compound of formulaIV obtained. For example, replacement withN-[[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]carbonyl]-N-methylglycinemethyl ester, NMR(CDCl₃) δ2.85 (s, 3H), 3.5-4.5 (m, 2H), 3.4 and 3.75(2s, 6H), 7.0-8.4 (m,5H), prepared according to the procedure of example2, givesN-[[5-(trifluoromethyl)-6-methoxy-1-naphthanenyl]carbonyl]-N-methylglycine,mp 174°-175° C.; NMR(DMSO-d₆) δ2.75 and 3.1 (2s, 3H), 4.03 (s, 3H), 4.30(d, 2H), 7.8 (m, 5H); IR (Nujol *) 2500, 1720 with inflection at 1745,1580 cm⁻¹ ; UVλmax (EtOH) 335 nm (ε3,050), 322 (2,700), 295 (5,100), 283(5,750), 275 (4,450), 220 (57,100); Anal Calcd: C, 56.30% H, 4.13% N,4.10%; Found: C, 55.29% H, 4.02% N, 3.99%.

EXAMPLE 61

4,6-Dimethoxy-1-naphthalenecarboxylic Acid (V, R³ =4-CH₃ O, R⁴ =6-CH₃ Oand R⁵ =H)

A stream of chlorine gas was passed through a cooled solution of NaOH(17.28 g, 0.432 mole) in water (24 ml) containing 100 g of ice until12.7 g (0.18 mole) of chlorine was absorbed into the solution. Solid(4,6-dimethoxy-1-naphthalenyl)ethanone [9.2 g, 0.04 mole, described byN. P. Buu-Hoi, J. Org. Chem., 21, 1257 (1956)], was added at 20°-22° C.to the chlorine solution. The mixture was stirred at 65° C. for one hr,cooled in an ice bath and treated with NaHSO₃ (5 g) in water (20 ml).The mixture was made neutral by the addition of dilute HCl. Theresulting precipitate was collected, washed well with water, dried overP₂ O₅ and recrystallized from methanol to give4,6-dimethoxy-1-naphthalenecarboxylic acid (7.0 g); mp 227°-229° C.;NMR(DMSO-d₆) δ3.85 (s, 3H), 4.0 (s, 3H), 7.7 (m, 5H); IR (white mineraloil) 2900, 1670 cm⁻¹ ; UVλmax (MeOH) 339 nm (ε4,910), 328 (4500), 304(8,180), 240 (40,100); Anal Calcd: C, 67.23% H, 5.21%; Found: C, 67.15%H, 5.23%.

EXAMPLE 62

4,6-Dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic Acid (V, R³=4-CH₃ O, R⁴ =5-CF₃ and R⁵ =6-CH₃ O)

4,6-Dimethoxy-1-naphthalenecarboxylic acid (98.5 g, 0.425 mole,described in Example 61) was added to an ice-cooled solution of SOCl₂(59.5 g, 0.5 mole) in anhydrous methanol (225 ml). The mixture washeated at reflux for 18 hr. Another portion of SOCl₂ (35.5 ml) was addedand the reflux was continued for another 7 hr. The mixture was extractedwith diethyl ether. The ether extract was washed with water and thenaqueous NaHCO₃ solution, dried (Na₂ SO₄) and concentrated to dryness.The solid residue was crystallized from methanol (720 ml) to give 64.5 gof 4,6-dimethoxy-1-naphthalenecarboxylic acid methyl ester; mp 102°-104°C.; NMR(CDCl₃) δ3.9 (s, 6H), 4.0 (s, 3H), 7.7 (m, 5H).

The latter compound (4.93 g, 0.02 mole) was suspended in 20% (v/v)aqueous acetic acid and concentrated H₂ SO₄ (0.279 ml). The mixture wasstirred and heated at 60° C. Iodine (2 g, 0.008 mole) and periodic acid(2.76 g, 0.012 mole) was added to the mixture. The reaction mixture wasstirred for one hr at the same temperature, cooled, poured into waterand extracted with chloroform. The chloroform extract was washed withaqueous sodium bisulphite solution, washed with water and dried (Na₂SO₄). The chloroform extract was poured onto a column of 250 g of silicagel (prepared with 10% (v/v) ethyl acetate in hexane). The column waseluted with 1.5 liters of the same solvent system and then with 20%(v/v) ethyl acetate in hexane. The appropriate fractions were combinedto give 5-iodo-4,6-dimethoxy-1-naphthalenecarboxylic acid methyl ester(1.4 g, 80% pure). The pure compound, mp 120°-122° C., was obtained bycrystallization from ethyl acetate-hexane.

A mixture of the latter compound (7.1 g, 0.019 mole), freshly preparedcopper powder (4.5 g, prepared according to the procedure of R. Q.Brewster and T. Groening, "Organic Synthesis", Coll. Vol. II, John Wileyand Sons, New York, N.Y., U.S.A., 1948, p. 445), trifluoromethyl iodide(8.5 g, 0.43 mole) and dry pyridine (35 ml) was heated for 20 hr at 120°C. in an autoclave. After cooling to 22° to 24° C., the mixture wastaken up in toluene and the toluene suspension was filtered. Thefiltrate was concentrated to dryness under reduced pressure. The residuewas dissolved in chloroform. Insoluble material in the chloroformsolution was removed by filtration. The filtrate was passed through acolumn of 75 g of silica gel and the column was eluted with chloroform.The pure fractions were combined and crystallized from ethylacetate-hexane to give 2.83 g of4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid methylester; mp 120°-123° C., NMR(CDCl₃) δ3.95 (m, 9H), 6.8 and 8.05 (2d, J=10Hz, 2H), 7.21 and 9.1 (2d, J=10 Hz, 2H).

A suspension of the latter compound (2.83 g, 0.009 mol) in methanol(16.2 ml) and NaOH (5.4 ml of a 4N aqueous solution) was heated atreflux under nitrogen for 10 min. The resulting clear solution wascooled in an ice bath and rendered acid (pH=3) with 2N aqueous HCl. Theprecipitate was collected, washed with water and dried over P₂ O₅ togive 2.7 g of the title compound, m/e 300 (M⁺).

EXAMPLE 63

By following serially the procedures of examples 2 and 3 and using anequivalent amount of 4,6-dimethoxy-1-naphthalenecarboxylic acid ofexample 61 instead of 5-bromo-1-naphthalenecarboxylic acid;N-[(4,6-dimethoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methylester (I, R¹ and R² =CH₃, R³ =4-CH₃ O, R⁴ =6-CH₃ O and R⁵ =H); mp105°-107° C.; NMR(CDCl₃) δ3.05 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.0(s, 3H), 4.8 (2d, J=20 Hz, 2H), 7.3 (m, 5H); was obtained viaN-[(4,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester;NMR(CDCl₃) δ2.75 (s, 3H), 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (s, 3H), 4.35(s, 2H), 7.4 (m, 5H).

By following serially the procedures of examples 2 and 3 and using anequivalent amount of 6-methoxy-1-naphthalenecarboxylic acid, describedby C. C. Price et al., J. Am. Chem. Soc., 69, 2261 (1947), instead of5-bromo-1-naphthalenecarboxylic acid,N-[(6-methoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester(I, R¹ and R² =CH₃, R³ =6-methoxy, and R⁴ and R⁵ =H), NMR(CDCl₃) δ3.02(s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 4.53 and 4.35 (d, J=17 Hz, 2H),6.90-8.10 (m, 6H), was obtained viaN-[(6-methoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester.

By following serially the procedures of examples 2 and 3 and using anequivalent amount of4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid ofexample 62, instead of 5-bromo-1-naphthalenecarboxylic acid;N-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycinemethyl ester (I, R¹ and R² =CH₃ O, R³ =4-CH₃ O, R⁴ =5-CF₃ and R⁵ =6-CH₃O), NMR(CDCl₃) δ3.0 (s, 3H), 3.7 (s, 3H), 3.85 (s, 3H), 3.95 (s, 3H),4.35 and 5.45 (2d, J=17 Hz, 2H), 6.8-8.2 (m, 4H), was obtained viaN-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycinemethyl ester, NMR(CDCl₃) δ2.78 (s, 3H), 3.6 (s, 3H), 3.85 (s, 3H), 3.9(s, 3H), 4.35 (m, 2 H), 6.7-8.3 (m, 4H).

EXAMPLE 64

By following the procedure of example 32, but replacingN-[(5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl esterwith an equivalent amount of one of the ester compound of formula I inwhich R² is lower alkyl, described in example 63, the correspondingcompound of formula I in which R² is hydrogen was obtained, namely,N-[(4,6-dimethoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine;NMR(DMSO-d₆) δ3.05 (s, 3H), 3.90 (s, 3H), 3.97 (s, 3H), 4.27 and 4.67(2d, J=17 Hz, 2H), 6.50-8.00 (m, 5H), 9.12 (broad, 1H); IR (CHCl₃) 2900,1720 cm⁻¹ ; UVλmax (MeOH) 337 nm (ε10,280), 322 (9,675), 278 (35,385)shoulder at 242 (66,830), 224 (114,600); Anal Calcd: C, 60.17% H, 5.36%N, 4.38%; Found: C, 58.38% H, 5.20 % N, 4.80%;N-[(6-methoxy-1-naphthalenyl)-thioxomethyl]-N-methylglycine; mp153°-154° C., NMR(DMSO-d₆) δ2.95 (s, 3H), 3.9 (s, 3H), 4.65 and 5.2 (2d,J=16.5 Hz, 2H), 7.5 (m, 6H); andN-[[4,6-dimethoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine;NMR(CDCl₃) δ3.05 (s, 3H), 3.9 (s, 3H), 3.95 (s, 3H), 4.5 and 5.11 (2d,J=17 Hz, 2H), 6.75 (s, 1H), 7.2 (m, 4H); IR (CHCl₃) 3000, 1720, 1270,1130 cm⁻¹ ; Anal Calcd: C, 52.70% H, 4.16% N, 3.61%; Found: C, 52.83% H,4.46% N, 3.57%.

We claim:
 1. A compound of the formula ##STR5## wherein R¹ is loweralkyl, lower alkenyl or phenylmethyl; R³ is a substituent at position 4,5 or 8 of the naphthalene ring, the substituent being selected from thegroup consisting of lower alkyl, lower alkoxy, halo, cyano, nitro andtrihalomethyl, and R⁴ and R⁵ each is hydrogen; or R³ and R⁴ each is asubstituent at different positions of the naphthalene ring, thepositions selected from positions 3 to 7 and the substituents beingselected from the group consisting of lower alkyl, lower alkoxy, halo,trihalomethyl, (lower)-alkoxy(lower)alkoxy, phenylmethoxy andphenylmethoxy substituted on the phenyl portion with a lower alkyl,lower alkoxy, halo or trihalomethyl and R⁵ is hydrogen; or R³, R⁴ and R⁵each is a substituent at different positions selected from positions 4,5 and 6 of the naphthalene ring, the substituent being selected from thegroup consisting of lower alkoxy, halo and trihalomethlyl; and R ishydrogen or lower alkyl.